Process for improved oxymorphone synthesis

ABSTRACT

Processes for preparing oxymorphone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxymorphinone salt in the presence of trifluoroacetic acid and/or a glycol.

The present invention is in the field of oxymorphone synthesis. Itprovides processes for preparing oxymorphone, in particular oxymorphonebase. The resulting oxymorphone base may be used in the preparation ofAPIs like oxymorphone hydrochloride. Said APIs may be used inpharmaceutical dosage forms.

BACKGROUND OF THE INVENTION

Oxymorphone and its hydrochloride salt have long been used asanalgesics.

Oxymorphone base is conventionally prepared by O-demethylation ofoxycodone. Oxymorphone base can also be prepared by oxidation oforipavine to 14-hydroxymorphinone, and reducing the 14-hydroxymorphinoneto oxymorphone base. A route for the preparation of oxymorphone viaoxidation of oripavine to 14-hydroxymorphinone is illustrated in Scheme1:

Once the oxymorphone base has been prepared, it is usually reacted withan acid to produce an oxymorphone salt, typically oxymorphonehydrochloride (which is the API form in which oxymorphone is generallyused therapeutically), as shown below in Scheme 2:

The oxidation step in the synthetic route illustrated in Scheme 1 canyield by-products which may be converted into other by-products duringfurther conversion of the oxidation product (e.g., during the reactionshown in Scheme 2) or may be carried over into the final oxymorphonesalt or other opioid made from the oxymorphone base, finalpharmaceutical composition or final dosage form. These by-products maybe undesired in the final pharmaceutical composition or final dosageform. Separation of these by-products from the final product may oftenbe difficult, time-consuming and not volume efficient (e.g., if aseparation by HPLC is required).

For example, during oxidation of oripavine to 14-hydroxymorphinone,certain by-products can be formed, in particular 8-hydroxyoxymorphone:

The 8-hydroxyoxymorphone can be converted to 14-hydroxymorphinone whenHCl is added, as illustrated in Scheme 4:

Thus, the 14-hydroxymorphinone intermediate shown in Scheme 1 is notonly the immediate precursor to oxymorphone, it is also often found inthe final oxymorphone salt used in pharmaceutical compositions, which isusually oxymorphone hydrochloride. 14-hydroxymorphinone belongs to aclass of compounds known as α,β-unsaturated ketones (ABUKs). Thesecompounds contain a substructural component (the α,β-unsaturated ketonecomponent) which produces a structure-activity relationship alert forgenotoxicity. Their presence may be undesired in a pharmaceuticalcomposition. Some regulatory authorities do not approve a pharmaceuticalcomposition or dosage form for use and sale to the public if the amountof ABUKs in the pharmaceutical composition or dosage form exceeds theamount set by these authorities.

In PCT/IB2013/001541 reactions are described which allow reduction ofthe amount of undesired by-products caused by the oxidation step. Inparticular, PCT/IB2013/001541 describes the performance of the oxidationreaction in the presence of an acid H_(n)X^(n−), e.g. H₂SO₄, such that a14-hydroxymorphinone salt with X^(n−), e.g. SO₄ ²⁻, as counterion isformed:

However, even under these reaction conditions, some 8-hydroxyoxymorphonemight be carried over into oxymorphone in a subsequent reductionreaction.

Even in spite of the improvements achieved by recent developments likethe processes described in PCT/IB2013/001541, there is still acontinuing need for processes for preparing oxymorphone which exhibit areduced amount of by-products in the final product. In particular, aprocess for preparing oxymorphone base with a reduced amount of8-hydroxyoxymorphone, preferably with no (detectable)8-hydroxyoxymorphone would be advantageous.

SUMMARY OF THE INVENTION

The present invention provides a hydrogenation process for preparingoxymorphone from 14-hydroxymorphinone, which process is suitable toreduce or even completely suppress the presence of undesired byproductsof the oxidation reaction leading from oripavine to14-hydroxymorphinone, in particular of 8-hydroxyoxymorphone, in theresulting oxymorphone.

The hydrogenation process according to the invention is useful forpreparing oxymorphone base from 14-hydroxymorphinone sulfate which wasmade via an oxidation process as described above. Even if this startingmaterial contains 8-hydroxyoxymorphone, the resulting oxymorphone basemade via the hydrogenation process according to the invention containsvery small amounts or even no detectable amounts of8-hydroxyoxymorphone. It also contains very small amounts or even nodetectable amounts of 14-hydroxymorphinone, which can be formed from8-hydroxyoxymorphone under acidic conditions (like the acidic conditionsof the hydrogenation process).

In one aspect, the present invention provides a process for preparingoxymorphone or an (optionally pharmaceutically acceptable) salt orsolvate thereof, the process comprising or consisting of a conversion ofa 14-hydroxymorphinone salt or a solvate thereof to oxymorphone or saltor solvate thereof, by hydrogenation of the 14-hydroxymorphinone salt orsolvate thereof in the presence of trifluoroacetic acid (abbreviated as“TFA”) and/or a glycol. Preferably, both trifluoroacetic acid and aglycol are present during the hydrogenation. In said process, the14-hydroxymorphinone salt or a solvate thereof may be used as a startingmaterial or as an intermediate material. In each of these cases, said14-hydroxymorphinone salt or solvate thereof may be prepared by thefollowing process starting from oripavine as described inPCT/IB2013/001541 (see also detailed description of the presentinvention below):

The process for preparing oxymorphone or an (optionally pharmaceuticallyacceptable) salt or solvate thereof according to the present inventionis represented by the following reaction Scheme 7:

wherein

-   X^(n−) is an anion selected from the group consisting of Cl⁻, HSO₄    ⁻, SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻,    HPO₄ ²⁻, PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof; and-   n is 1, 2, or 3.

Preferably, X^(n−) is SO₄ ²⁻. So, the 14-hydroxymorphinone salt ispreferably 14-hydroxymorphinone sulfate.

Given the ingredients of the hydrogenation reaction, depending on thesubsequent workup the resulting oxymorphone could be isolated (1) asfree base, (2) as salt with X^(n−) as anion, (3) as oxymorphonetrifluoroacetate, or (4) as a salt with a combination of X^(n−) andtrifluoroacetate as anion. In a preferred embodiment of the presentinvention, it is isolated as free base.

The 14-hydroxymorphinone salt is represented by the following structure:

wherein X^(n−) and n are defined as above.

In one embodiment, the 14-hydroxymorphinone salt is

or a solvate thereof. In the context of the present invention, thiscompound will be designated as 14-hydroxymorphinone sulfate. Because ofits stoichiometric composition, it may also be designated asbis(14-hydroxymorphinone)sulfate. The terms 14-hydroxymorphinone sulfateand bis(14-hydroxymorphinone)sulfate are used interchangeably in thecontext of the present invention.

In the 14-hydroxymorphinone salt, the 14-hydroxymorphinone is typicallyprotonated by a proton (H⁺), and thus forms a cation. For example, whenn=2, the two protons and two molecules of 14-hydroxymorphinone which arepresent in the 14-hydroxymorphinone salt form two cations of14-hydroxymorphinone in its protonated form.

According to the present invention, the hydrogenation is performed inthe presence of trifluoroacetic acid and/or a glycol. In a preferredembodiment, TFA is present, and preferably in a substoichiometricamount. In another preferred embodiment, glycol is present. Even morepreferably, both glycol and TFA are present, wherein TFA is preferablypresent in a substoichiometric amount.

Preferably, the glycol is selected from the group consisting of ethyleneglycol, propylene glycol, 1,3-propanediol, 1,2-butanediol,1,3-butanediol, neopentylglycol, and mixtures thereof. More preferably,the glycol is ethylene glycol, propylene glycol, or a mixture thereof.

The advantages of the hydrogenation reaction characterizing the processof the present invention are explained in the following: The presence oftrifluoroacetic acid and glycol during hydrogenation has the technicaleffect that less 8-hydroxyoxymorphone will be present in the reactionproduct than in a reaction product made in the absence oftrifluoroacetic acid and glycol. As shown in Example 16, by performingthe hydrogenation in the presence of trifluoroacetic acid and glycol,even oxymorphone without any detectable amount of 8-hydroxyoxymorphoneor 14-hydroxymorphinone can be prepared from a starting materialcontaining 8-hydroxyoxymorphone. Said 8-hydroxyoxymorphone is anundesired by-product of the oxidation of oripavine to14-hydroxymorphinone, and it is carried over into the final oxymorphonein conventional reduction reactions leading from 14-hydroxymorphinone(made by oxidation of oripavine) to oxymorphone. The hydrogenationreaction of the present invention can reduce or even completely suppressthis carryover. Without being bound by theory, the reaction conditionsof the hydrogenation reaction, in particular the low content of acid(typically a substoichiometric amount of TFA is used) in the reactionmixture, might also prevent acid-catalyzed conversion of14-hydroxymorphinone into 8-hydroxyoxymorphone during the hydrogenationreaction. Moreover, 8-hydroxyoxymorphone might be more soluble in thereaction solvent (which contains the glycol characterizing thehydrogenation reaction of the present invention) than oxymorphone baseor an oxymorphone salt. Thus, oxymorphone or a salt thereof can bepurified from 8-hydroxyoxymorphone by precipitation. A preferredembodiment of the present invention makes use of this effect byprecipitating and isolating the oxymorphone base.

Processes using a 14-hydroxymorphinone trifluoroacetate salt as startingmaterial for a reduction reaction are already described inPCT/IB2013/001541. However, for performing the process of the presentapplication, it is sufficient to use trifluoroacetic acid insubstoichiometric amounts (less than 1 molar equivalent of14-hydroxymorphinone), together with a different 14-hydroxymorphinonesalt, e.g., 14-hydroxymorphinone sulfate.

In certain embodiments, trifluoroacetic acid is the sole acid added tothe hydrogenation reaction mixture, and it is added in substoichiometricamounts, i.e. less than 100 mol % of the 14-hydroxymorphinone in thestarting material 14-hydroxymorphinone salt. This can greatly reduce theamount of base which has to be added to precipitate the oxymorphone freebase after the hydrogenation reaction. As already mentioned above, thislow amount of acid in the reaction mixture might also preventacid-catalyzed conversion of 14-hydroxymorphinone into8-hydroxyoxymorphone during the hydrogenation reaction.

A process according to the present invention comprises the steps ofproviding a solution or suspension of the 14-hydroxymorphinone salt or asolvate thereof; adding trifluoroacetic acid and/or a glycol; andsubsequently hydrogenating the 14-hydroxymorphinone to the oxymorphone,which may then be isolated as its base or as an (optionallypharmaceutically acceptable) salt or solvate thereof.

Hence, the present invention provides a process for preparingoxymorphone or a salt or solvate thereof from a 14-hydroxymorphinonesalt or a solvate thereof

the process comprising or consisting of the steps of

-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol, preferably    trifluoroacetic acid and a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to oxymorphone,    wherein X^(n−) and n are defined as above.

After the hydrogenation reaction, the oxymorphone may be present as itssalt or solvate in the reaction mixture, e.g., as its sulfate saltand/or trifluoroacetate salt. In a subsequent step, it may be convertedinto its free base and/or converted into a different salt or solvate,e.g., a pharmaceutically acceptable salt or solvate. It may be isolatedfrom the reaction mixture in one or more of these forms.

In a preferred embodiment, the oxymorphone is isolated from the reactionmixture as free base, e.g. by precipitation and subsequent isolation ofthe precipitate. In said embodiment, the process may be represented bythe following reaction scheme:

the process comprising or consisting of the steps of

-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol, preferably    trifluoroacetic acid and a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to the oxymorphone; and-   (d) adding a base, thus raising the pH to a pH where the oxymorphone    precipitates, and isolating the oxymorphone as its free base or a    solvate thereof,    wherein X^(n−) and n are defined as above, and X^(n−) is preferably    SO₄ ²⁻.

In a preferred aspect of this process, 14-hydroxymorphinone sulfate (ora solvate thereof) is converted into oxymorphone base (or a solvatethereof).

Usually, the oxymorphone resulting from a conventional reduction of a14-hydroxymorphinone salt (e.g., 14-hydroxymorphinone sulfate) maycontain certain by-products, as shown in the following Scheme 8:

8-Hydroxyoxymorphone is undesired in the final oxymorphone because itmay convert to 14-hydroxymorphinone, an ABUK, under acidic conditions,in particular when oxymorphone is converted to oxymorphone hydrochloride(the API). Apart from 8-hydroxyoxymorphone, 14-hydroxymorphinone is alsoundesired in the final oxymorphone. Such 14-hydroxymorphinone may beunreacted starting material, or it may be formed from8-hydroxyoxymorphone because of the presence of acid in thehydrogenation mixture during the hydrogenation or after thehydrogenation reaction has been stopped. It is an advantage of thepresent invention that the hydrogenation reaction according to thepresent invention allows formation of oxymorphone which does neithercontain 14-hydroxymorphinone nor 8-hydroxyoxymorphone.

The hydrogenation reaction characterizing the process of the presentinvention is suitable for reducing the amount of 8-hydroxyoxymorphoneand/or 14-hydroxymorphinone in the resulting oxymorphone or salt orsolvate thereof, in comparison to processes utilizing a differentreduction or hydrogenation reaction which also starts with14-hydroxymorphinone salt as starting material, and especially incomparison to processes not utilizing a salt of 14-hydroxymorphinone, inparticular not 14-hydroxymorphinone sulfate, as starting material.

The hydrogenation process of the present invention differs from thehydrogenation described in PCT/IB2013/001541 and similar prior arthydrogenations in that TFA and/or glycol, preferably both TFA and glycolare present during the hydrogenation. This has the surprising effectthat the resulting oxymorphone base contains very small amounts or evenno detectable amounts of 8-hydroxyoxymorphone. It also contains verysmall amounts or even no detectable amounts of 14-hydroxymorphinone,which can be formed from 8-hydroxyoxymorphone under acidic conditions(like the acidic conditions of the hydrogenation process).

It may also be because of the use of the 14-hydroxymorphinone salt asstarting material for said hydrogenation reaction that the process ofthe present invention is suitable for reducing the amount of14-hydroxymorphinone and/or 8-hydroxyoxymorphone in oxymorphone or asalt or solvate thereof prepared from said 14-hydroxymorphinone salt, incomparison to processes using other intermediates or starting materials.14-hydroxymorphinone salt made from oripavine, e.g. according to theprocesses described in PCT/IB2013/001541, contains reduced amounts of8-hydroxyoxymorphone in comparison to 14-hydroxymorphinone made viaother routes from oripavine. The lower amount of 8-hydroxyoxymorphone inthe 14-hydroxymorphinone salt may result in less 8-hydroxyoxymorphone inoxymorphone made from said 14-hydroxymorphinone salt, which in turn mayresult in less 14-hydroxymorphinone in an oxymorphone salt made fromsaid oxymorphone, because 14-hydroxymorphinone can be formed from8-hydroxyoxymorphone during the conversion of oxymorphone to a saltthereof by acid addition.

In those embodiments of the present invention which encompassprecipitation and isolation of the oxymorphone as free base, typically,at least some 8-hydroxyoxymorphone or salt or solvate thereof remains inthe supernatant. Thus, a separation of the 8-hydroxyoxymorphone from theoxymorphone or solvate thereof may be achieved by the precipitation. Theprecipitated and optionally isolated precipitate, which contains theoxymorphone base or the solvate thereof, may contain a lower ratio ofthe 8-hydroxyoxyomrphone to the oxymorphone than the ratio of the8-hydroxyoxymorphone to the oxymorphone in the mother liquor.

8-hydroxyoxymorphone has the following formula:

The stereoconfiguration at C-8 of 8-hydroxyoxymorphone can be eitheralpha (8α) or beta (8β). The 8α and 8β stereoconfiguration are shown for8-hydroxyoxymorphone in Scheme 9. The 8-hydroxyoxymorphone may be the 8αcompound, or the 8β compound, or a mixture of the 8α-hydroxyoxymorphoneand the 8β-hydroxyoxymorphone.

Pharmaceutical compositions prepared by processes of the presentinvention may be quantitatively different from pharmaceuticalcompositions prepared by conventional processes which do not utilize thehydrogenation of 14-hydroxymorphinone salt according to the presentinvention, and may offer advantages over the compositions prepared byconventional processes, e.g., in terms of safety, efficiency and reducedmanufacturing costs. For example, these compositions may contain lessby-products and/or require less or no further processing steps aftersynthesis of their API.

Moreover, the hydrogenation reaction according to the present inventionmay allow for a more volume efficient process, as compared to theconventional hydrogenation reaction. The use of a substoichiometricamount of trifluoroacetic acid (instead of, e.g. formic acid as anexcess reagent as described in conventional hydrogenation reactions,which generally use >5 molar equivalents of formic acid) requires theaddition of less base after the hydrogenation if the oxymorphone shallbe precipitated as its free base. This reduces the amount of baserequired, and also makes the reaction more volume efficient.

Oxymorphone or an (optionally pharmaceutically acceptable) salt orsolvate thereof are also provided by the present invention. Oxymorphone,when prepared by a process according to present invention, may compriseonly very low amounts of 8-hydroxyoxymorphone and/or14-hydroxymorphinone. As explained above, under the conditions describedin the prior art, 14-hydroxymorphinone may be formed from8-hydroxyoxymorphone when preparing the oxymorphone or a salt or solvatethereof. In particular, the oxymorphone or the pharmaceuticallyacceptable salt or solvate thereof according to the present inventionmay comprise an amount of 14-hydroxymorphinone which is below a desiredthreshold amount, e.g., a threshold amount mandated by the regulatoryauthorities for the approval of pharmaceutical compositions for use andsale to the public, and/or it comprises an amount of8-hydroxyoxymorphone which is insufficient to increase the amount of14-hydroxymorphinone or a salt or solvate thereof, upon furtherprocessing of the oxymorphone or a salt or solvate thereof, above saidthreshold amount.

The present invention further provides pharmaceutical compositions anddosage forms, which comprise oxymorphone or a pharmaceuticallyacceptable salt or solvate thereof (e.g., oxymorphone hydrochloride).Said oxymorphone is preferably prepared by the process according to thepresent invention. In certain embodiments, these pharmaceuticalcompositions have a different by-product profile and may have adifferent efficacy than pharmaceutical compositions prepared via adifferent reduction reaction, rather than via the hydrogenation reactionof the present invention. In particular, the content of the14-hydroxymorphinone in these pharmaceutical compositions differs fromthe content of the 14-hydroxymorphinone in pharmaceutical compositionsprepared via the free base of 14-hydroxymorphinone, rather than via the14-hydroxymorphinone salt or a solvate thereof. This encompassespharmaceutical compositions comprising oxymorphone or thepharmaceutically acceptable salt or solvate thereof and14-hydroxymorphinone or a salt or solvate thereof in an amount which isbelow a desired threshold amount, e.g., a threshold amount mandated bythe regulatory authorities for the approval of these compositions foruse and sale to the public. It also encompasses pharmaceuticalcompositions comprising, in addition to the oxymorphone or thepharmaceutically acceptable salt or solvate thereof,8-hydroxyoxymorphone or a salt or solvate thereof in an amount which isinsufficient to increase the levels of 14-hydroxymorphinone or a salt orsolvate thereof, upon further processing of the pharmaceuticalcomposition, above said desired threshold amount of the14-hydroxymorphinone. It also encompasses pharmaceutical compositionscomprising, in addition to the oxymorphone or the pharmaceuticallyacceptable salt or solvate thereof, 14-hydroxymorphinone or a salt orsolvate thereof, and 8-hydroxyoxymorphone or a salt or solvate thereof,wherein the 8-hydroxyoxymorphone is present in an amount which isinsufficient to increase the levels of the 14-hydroxymorphinone, uponfurther processing as described in the prior art, above said desiredthreshold amount.

The present invention is further directed to pharmaceutical compositionsand dosage forms formed as the result of carrying out the processes ofthe invention, as well as methods for using these pharmaceuticalcompositions and dosage forms in the treatment of medical conditions.The immediate products formed by carrying out the processes of theinvention may be suitable as pharmaceutical compositions themselves,without further processing steps.

These pharmaceutical compositions and dosage forms can be used to treator prevent one or more of the following medical conditions: pain,addiction, cough, constipation, diarrhea, insomnia associated withand/or caused by pain, cough or addiction, depression associated withand/or resulting from pain, cough or addiction, or a combination of twoor more of the foregoing conditions, etc. A method for treatment orprevention of one or more of these conditions by administration ofoxymorphone or a salt or solvate thereof to a patient is also providedby the present invention.

The use of a pharmaceutical composition or dosage form according to thepresent invention, comprising oxymorphone or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor the treatment of one or more of these medical conditions is alsopart of the present invention.

Certain Embodiments of the Invention

The present invention encompasses the following embodiments:

-   (1) A process for preparing oxymorphone or a salt or solvate thereof    from a 14-hydroxymorphinone salt or a solvate thereof

the process comprising or consisting of the steps of

-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to the oxymorphone,    wherein-   X^(n−) is an anion selected from the group consisting of Cl⁻, HSO₄    ⁻, SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻,    HPO₄ ²⁻, PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof; and-   n is 1, 2, or 3.-   (2) The process of (1), wherein trifluoroacetic acid and a glycol    are added in step (b).-   (3) The process of (1) or (2), wherein n is 2 and X^(n−) is SO₄ ²⁻.-   (4) The process of any one of (1) to (3), wherein the amount of    trifluoroacetic acid is 99 mol % or less as compared to the molar    amount of 14-hydroxymorphinone contained in the 14-hydroxymorphinone    salt.-   (5) The process of (4), wherein the amount of trifluoroacetic acid    is from 30 mol % to 50 mol % as compared to the molar amount of    14-hydroxymorphinone contained in the 14-hydroxymorphinone salt.-   (6) The process of any one of (1) to (5), wherein the glycol is    selected from the group consisting of ethylene glycol, propylene    glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol,    neopentylglycol, and mixtures thereof.-   (7) The process of (6), wherein the glycol is ethylene glycol,    propylene glycol, or a mixture thereof.-   (8) The process of (7), wherein the glycol is ethylene glycol.-   (9) The process of (7), wherein the glycol is propylene glycol.-   (10) The process of any one of (1) to (9), wherein the glycol added    in step (b) is in the range of 1 to 8 volumes in mL in relation to    the weight in g of the 14-hydroxymorphinone salt.-   (11) The process of any one of (1) to (10), wherein the    hydrogenation in step (c) is performed with H₂ and a hydrogenation    catalyst.-   (12) The process of (11), wherein the hydrogenation catalyst is    Pd/C.-   (13) The process of any one of (1) to (12), wherein a mixture of    water and the glycol is used as solvent.-   (14) The process of (13), wherein the mixture is in a range from    20:80 to 45:55 glycol:water.-   (15) The process of (14), wherein the mixture is about 40:60    glycol:water.-   (16) The process of any one of (1) to (15), additionally comprising    the step:-   (d) adding a base, thus raising the pH to a pH where the oxymorphone    precipitates as its free base, and isolating the oxymorphone as its    free base or a solvate thereof.-   (17) The process of (16), wherein the base added in step (d) is    NaOH.-   (18) A process for preparing oxymorphone or a salt or solvate    thereof from oripavine, the process comprising or consisting of the    steps

-   (aa) oxidizing the oripavine to 14-hydroxymorphinone;-   (bb) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before,    during and/or after the oxidation reaction;-   (cc) optionally precipitating the resulting 14-hydroxymorphinone as    14-hydroxymorphinone salt or a solvate thereof;-   (dd) optionally isolating the precipitated 14-hydroxymorphinone salt    or solvate thereof; and-   (ee) performing the process according to any one of (1) to (17),    wherein-   X^(n−) is an anion selected from the group consisting of Cl⁻, HSO₄    ⁻, SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻,    HPO₄ ²⁻, PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof; and-   n is 1, 2, or 3.-   (19) The process of (18), wherein n is 2 and X^(n−) is SO₄ ²⁻.-   (20) The process of (1), wherein said process comprises the steps of-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to the oxymorphone.-   (21) The process of (1), wherein said process consists of the steps    of-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to the oxymorphone.-   (22) The process of (18), wherein said process comprises the steps

-   (aa) oxidizing the oripavine to 14-hydroxymorphinone;-   (bb) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before,    during and/or after the oxidation reaction;-   (cc) optionally precipitating the resulting 14-hydroxymorphinone as    14-hydroxymorphinone salt or a solvate thereof;-   (dd) optionally isolating the precipitated 14-hydroxymorphinone salt    or solvate thereof; and-   (ee) performing the process according to any one of (1) to (17).-   (23) The process of (18), wherein said process consists of the steps

-   (aa) oxidizing the oripavine to 14-hydroxymorphinone;-   (bb) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before,    during and/or after the oxidation reaction;-   (cc) optionally precipitating the resulting 14-hydroxymorphinone as    14-hydroxymorphinone salt or a solvate thereof;-   (dd) optionally isolating the precipitated 14-hydroxymorphinone salt    or solvate thereof; and-   (ee) performing the process according to any one of (1) to (17).-   (24) Oxymorphone prepared by the process of any one of (1) to (23).-   (25) The oxymorphone of (24), which contains less than 1 ppm    8-hydroxyoxymorphone and less than 1 ppm 14-hydroxymorphinone.-   (26) A pharmaceutical composition comprising the oxymorphone    according to (24) or (25) and a pharmaceutically acceptable    excipient.-   (27) The oxymorphone of (24) or (25), or the pharmaceutical    composition of (26), for use in the treatment of pain.    Definitions

Unless otherwise specified, the following abbreviations and definitionsare used in the context of the present invention.

The undefined article “a” or “an” is intended to mean one or more of thespecies designated by the term following said article. For example, “acompound of formula II” encompasses one or more molecules of thecompound of formula II.

The term “about” in the context of the present application means a valuewithin 15% (±15%) of the value recited immediately after the term“about,” including any numeric value within this range, the value equalto the upper limit (i.e., +15%) and the value equal to the lower limit(i.e., −15%) of this range. For example, the phrase “about 100”encompasses any numeric value that is between 85 and 115, including 85and 115 (with the exception of “about 100%”, which always has an upperlimit of 100%). In a preferred aspect, “about” means ±10%, even morepreferably ±5%, even more preferably ±1% or less than ±1%.

“TFA” means trifluoroacetic acid.

An “opioid” in its broadest sense encompasses all compounds usuallydesignated with said term in the art, including opioids which act as anagonist on opioid receptors and opioids which act as an antagonist onopioid receptors. Partial agonists and partial antagonists are alsoknown and are encompassed by the term “opioid”. Opioid agonists include,e.g., oxymorphone, oxycodone, noroxymorphone, nalfurafine and salts andsolvates of any of the foregoing. Opioid antagonists include, e.g.,naltrexone, methylnaltrexone, naloxone, nalmefene, and salts andsolvates of any of the foregoing. In the context of the presentapplication, the term “opioid” shall encompass a compound having one ofthe following scaffolds (which will be designated as “morphine scaffold”in the context of present invention):

The degree of unsaturation in the ring formed by atoms 5, 6, 7, 8, 14and 13 may vary (the ring may, e.g., just contain single bonds as in8-hydroxyoxymorphone, contain just one double bond as in14-hydroxymorphinone, or contain two double bonds as in oripavine).

The “threshold amount” of 14-hydroxymorphinone in pharmaceuticalcompositions and dosage forms may be set by regulatory authorities suchas the U.S. Food and Drug Administration (FDA) and can then be learnedfrom the latest version of the FDA guidelines (“Guidelines”) or, if notaddressed in said Guidelines, from the latest version of the ICHGuidelines. In the context of the present invention, the thresholdamount may be 10 ppm or less.

The term “8-hydroxy compound” in the context of the present applicationmeans a compound containing a hydroxyl group in position 8 of themorphine scaffold. In a narrower sense, it means 8-hydroxyoxymorphone ora salt or solvate thereof. The term “8-hydroxy compound” includes the8α-hydroxyoxymorphone and/or the 8β-hydroxyoxymorphone.

It should be apparent to a person skilled in the art that the terms“salt” and “solvate” in the present specification encompass “apharmaceutically acceptable salt” and “a pharmaceutically acceptablesolvate”, respectively. The formation of a pharmaceutically acceptablesalt or solvate may be achieved either directly or by the preparation ofa pharmaceutically unacceptable salt or solvate and a subsequentconversion to the pharmaceutically acceptable salt or solvate. Aconversion of one pharmaceutically acceptable salt or solvate to anotherpharmaceutically acceptable salt or solvate is also possible.

The term “solvate” in the context of the present application in itsbroadest sense means an association product of a compound or salt of thepresent invention with a solvent molecule. The molar ratio of solventmolecule(s) per compound molecule may vary. The molar ratio of solventto compound/salt in the solvate may be 1 (e.g., in a monohydrate), morethan 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), or less than 1 (e.g.,0.5 in a hemihydrate). The molar ratio need not be an integer ratio, itcan also be, e.g., 0.5 (as in a hemihydrate) or 2.5. For example, 1molecule water per molecule of 14-hydroxymorphinone sulfate is bound in14-hydroxymorphinone sulfate monohydrate. Applied to oxymorphone,8-hydroxyoxymorphone, 14-hydroxymorphinone or, where appropriate, tosalts thereof, the solvate is in certain embodiments a hydrate, forexample a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrateor hexahydrate, or a hydrate wherein the ratio of water per molecule isnot necessarily an integer, but within the range of from 0.5 to 10.0. Incertain embodiments, the solvate is a hydrate wherein the ratio of waterper molecule is within the range of from 1 to 8. In certain embodiments,the solvate is a hydrate wherein the ratio of water per molecule iswithin the range of from 1 to 6, i.e. a mono- to hexahydrate. In certainembodiments, it is a monohydrate or a pentahydrate.

The terms “precipitating”/“precipitate”/“precipitation” in the contextof the present application shall encompass“crystallizing”/“crystallize”/“crystallization” unless stated otherwise.In certain embodiments, the precipitate described herein is amorphous.In certain embodiments, the precipitate is a mixture of amorphous andcrystalline components. In certain embodiments, the precipitatedescribed herein is crystalline. For example, 14-hydroxymorphinonesulfate may precipitate in a crystalline form, whilst oxymorphone basetypically is an amorphous precipitate.

The acronym “ppm” means parts per million. For purposes of the presentapplication, the numeric ppm amount values of opioids contained in acomposition containing more than one opioid are given in relation to theamount of the opioid (“reference opioid”) constituting the majority ofthe opioids contained in said composition. Such reference opioid willtypically be oxymorphone (in the final product oxymorphone of thehydrogenation reaction) or 14-hydroxymorphinone (in the startingmaterial 14-hydroxymorphinone salt of the hydrogenation reaction). Theppm values can be determined by performing a chromatographic resolutionof the composition and subsequent calculation of the relative orabsolute amounts of the opioid components based on the peak area. Forpurposes of the present invention, an HPLC method (e.g., as described inExample 11 for oxymorphone and its precursors and by-products) can beperformed. The composition components can be detected at a certainwavelength (e.g., at 292 nm for oxymorphone and its precursors andby-products). The HPLC peak area ratio of a certain opioid component tothe reference opioid determines the ppm value. The numeric ppm amountvalue of the one opioid compound constituting the majority of theopioids in the composition (i.e. of the reference opioid, which may beoxymorphone or 14-hydroxymorphinone) can be obtained from the percentarea of the peak of this compound in relation to the area sum of allopioid peaks.

Under the HPLC conditions used in the context of the present invention(e.g., the HPLC conditions as described in Example 11 for oxymorphoneand its precursors and by-products; or any other reverse phase HPLCconditions), any salt will not be determined in its salt form, but in adissociated form. For example, the 14-hydroxymorphinone moiety of14-hydroxymorphinone sulfate will be detected and quantified in itsdissolved form, i.e. as 14-hydroxymorphinone. Consequently, the HPLCpeak area detectable for an opioid salt of the present invention will bethe HPLC peak area which is detected for the opioid moiety comprised insaid salt. In case a salt contains more than one opioid moieties peranion, the HPLC method does not detect the absolute/relative amount ofthe salt itself, but of its opioid moiety. If in such a salt two opioidmoieties per anion are present (such as in 14-hydroxymorphinone sulfatewherein n is 2), the peak area detected in the HPLC is due to thepresence of the two opioid moieties contained in said salt. In case of a14-hydroxymorphinone salt wherein n is 3, the peak area detected in theHPLC is due to the presence of the three opioid moieties contained insaid 14-hydroxymorphinone salt.

This has the following consequence: As defined above, the numeric ppmvalue for an opioid is the ratio of peak area for said opioid inrelation to the peak area of the reference opioid. In case the presentapplication refers to numeric ppm values for a ratio of8-hydroxyoxymorphone to a 14-hydroxymorphinone salt, in fact the ratioof the peak area for the 8-hydroxymorphone to the peak area of the14-hydroxymorphinone (which is contained in the 14-hydroxymorphinonesalt) is provided. A 14-hydroxymorphinone salt comprises n-times thestructural unit of 14-hydroxymorphinone (e.g., two times for a sulfatesalt, three times for a phosphate salt, etc.). All ppm values given inthe description are based on the original peak area ratio of the opioidmoiety, without adjusting them by dividing them by n. For example, if apeak area ratio of 4 ppm is determined via HPLC for a14-hydroxymorphinone salt wherein n is 2, the corresponding ppm valuewill also be 4 (and not 2). This way of giving compound ratios in ppmwill be designated as “HPLC peak area ratio” in the following.

The opioid peaks which are typically considered in this determinationmethod are peaks having an UV-Vis spectrum which is typical for anopioid. For 14-hydroxymorphinone sulfate (or another14-hydroxymorphinone salt or solvate thereof) and for oxymorphone,typically the peaks of oxymorphone N-oxide, pseudo-oxymorphone (i.e.,2,2′-bisoxymorphone), 14-hydroxymorphine, 14-hydroxyisomorphine,10-ketooxymorphone, 14-hydroxymorphinone N-oxide, 10-hydroxyoxymorphone,8-hydroxyoxymorphone, 14-hydroxymorphinone, hydromorphone, oxymorphone,6α-oxymorphol, 6β-oxymorphol, oripavine, 8,14-dihydrooripavine,oxycodone (see, e.g., Example 11) may be considered (if present).However, not all of these peaks have to be considered. It is usuallysufficient to consider just some of them, for example8-hydroxyoxymorphone, 14-hydroxymorphinone, oxymorphone, 6α-oxymorphol,and oripavine.

A reverse phase HPLC method may be used for determination of ppm values.

The detection of the sample components may be performed using a UV/VISdetector, e.g., at a wavelength of 292 nm.

Alternatively, the detection of the sample components may be performedusing a mass spectrometer. The amount of a certain component may bedetermined by using a tritiated internal standard. However, this methodof detection does not require the “HPLC peak area ratio” describedabove, as it uses an internal standard.

In the preferred embodiments, a HPLC method described in Example 11 isused for determination of ppm values. In one embodiment, the HPLC methodof Example 11B is used.

“No detectable amount”, “not detectable” , “not . . . in detectableamounts” or a similar formulation means an amount of the compound inquestion (e.g. 14-hydroxymorphinone or 8-hydroxyoxymorphone) below theLOD (limit of detection). In the context of the present invention, thismeans an amount of less than 5 ppm, preferably less than 3 ppm, morepreferably less than 1 ppm of the compound in question (e.g.14-hydroxymorphinone or 8-hydroxyoxymorphone in relation to oxymorphone)(HPLC peak area ratio). In a specific aspect of the invention, this meanthe absence (i.e. 0 ppm) of the compound in question.

The term “API” in the context of the present invention means “activepharmaceutical ingredient” (e.g., oxymorphone hydrochloride) and shallbe used in its broadest sense as a synonym for a pharmaceutically activecompound in the context of the present invention. When an API is used inpreparing a pharmaceutical composition or dosage form, the API is thepharmaceutically active component of said pharmaceutical composition ordosage form. Pharmaceutical compositions or dosage forms containing anAPI may be approved by a governmental agency for sale and use in apatient (e.g., a human). Examples of APIs described in the context ofthe present invention include oxymorphone and oxymorphone hydrochloride.

The term “pharmaceutical composition” in the context of the presentapplication means a composition which contains an API and is suitablefor use in a patient (e.g., a human). It may be approved by agovernmental agency for sale and use in a patient. Examples forpharmaceutical compositions described in the context of the presentinvention are among the compositions containing oxymorphone oroxymorphone hydrochloride. Pharmaceutical compositions may becompositions prepared according to the invention if they comply withregulatory requirements for pharmaceutical compositions containing thesame API.

The term “salt” in the context of the present application means acompound comprising at least one cation (e.g., one or two14-hydroxymorphinone cations resulting from protonation of14-hydroxymorphinone (free base) by a Bronsted acid (like sulfuricacid)) and at least one anion (e.g., a sulfate anion). A salt may be theresult of the neutralization reaction between an acid and a base (e.g.,a Bronsted acid and a Bronsted base, or a Lewis acid and a Lewis base).In its solid form, the salt may have a crystalline structure. The term“salt” as used in the present application includes anhydrous, solvated,or hydrated forms of the salt. Whenever a solution or mixture containinga salt is mentioned, the term “salt” shall also encompass the dissolvedform of the salt. The term also encompasses pharmaceutically acceptablesalts, in particular when it refers to a salt of a compound which canserve as API. In the context of present invention, whenever a14-hydroxymorphinone salt is mentioned, this refers to a salt containinga 14-hydroxymorphinone cation, resulting, e.g., from protonation of the14-hydroxymorphinone. The same applies to other salts containing acation with a morphine scaffold, e.g., a salt of 8-hydroxyoxymorphone.An example for a 14-hydroxymorphinone salt is a salt which consists oftwo molecules of 14-hydroxymorphinone and one molecule of H₂SO₄, i.e.which comprises two 14-hydroxymorphinone cations per sulfate anion(14-hydroxymorphinone sulfate). In this salt, the cation results fromthe protonation of two molecules of 14-hydroxymorphinone and the anionis the resulting sulfate. In preferred embodiments of the presentinvention, a salt which is a 14-hydroxymorphinone salt is in its solidform. Another example for a salt is a salt of oxymorphone or a solvatethereof. An example for such salt of oxymorphone is a salt whichconsists of two molecules of oxymorphone and one molecule of H₂SO₄, i.e.which comprises two oxymorphone cations per sulfate anion (oxymorphonesulfate). In this salt, the cation results from the protonation of twomolecules of oxymorphone and the anion is the resulting sulfate. Inpreferred embodiments of the present invention, a salt of oxymorphone isin its solid form.

Whenever a compound or formula mentioned herein contains an atom orstructural element which could be a stereocenter (e.g., a chiral carbonatom or the morphine scaffold structure), it shall cover all possiblestereoisomers, unless indicated otherwise.

For compounds containing the morphine scaffold, the naturalstereoconfiguration of the morphine scaffold as shown in the followingshall be preferred:

wherein the degree of unsaturation in the ring formed by atoms 5, 6, 7,8, 14 and 13 may vary (the ring may, e.g., just contain single bonds asin 8-hydroxyoxymorphone, or contain just one double bond as in14-hydroxymorphinone, or contain two double bonds as in oripavine). Atposition 5, the following stereoconfiguration is preferred (exemplifiedfor the morphine scaffold of oripavine):

For the 8-hydroxy compounds, an α or a β configuration is possible atposition 8 as illustrated in the following:

In the compounds and compositions of the present invention, either bothconfigurations or only one configuration at position 8 may be present.

For all compounds containing a hydroxyl group at position 14, thefollowing stereoconfiguration occurs at position 14 as exemplified for14-hydroxymorphinone in the following:

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the auto-scaled chromatograph and peak results of theanalysis of the precipitated oxymorphone of Comparative Example 1.

FIG. 2 shows the auto-scaled chromatograph and peak results of theanalysis of the precipitated oxymorphone of Comparative Example 2.

FIG. 3 shows the auto-scaled chromatograph and peak results of theanalysis of the isolated solid oxymorphone of Comparative Example 10.

FIG. 4 shows a representative HPLC chromatogram for a standard mixtureof opioids resulting from the HPLC method of Example 11A. Legend: seeExample 11A.

FIG. 5 shows a representative HPLC chromatogram for a standard mixtureof opioids resulting from the HPLC method of Example 11B. Legend: seeExample 11B.

FIG. 6 shows the chromatogram of the analysis of the isolated solidoxymorphone of Example 16 for a sample concentration of 1 mg/mL.

FIG. 7 shows the chromatogram of the analysis of the isolated solidoxymorphone of Example 16 for a sample concentration of 10 mg/mL.

FIG. 8 shows the chromatogram of the analysis of the isolated solidoxymorphone of Example 17 for a sample concentration of 1 mg/mL.

FIG. 9 shows the chromatogram of the analysis of the isolated solidoxymorphone of Example 17 for a sample concentration of 10 mg/mL.

DETAILED DESCRIPTION OF THE INVENTION

I. Compounds

In the context of the present invention, compounds which are oripavine,oxymorphone, 14-hydroxymorphinone, 8-hydroxyoxymorphone, and salts andsolvates thereof, and mixtures of two or more of any of the foregoingcompounds are described. They may be used as starting materials,intermediates or products of the processes according to presentinvention. To these compounds, the following applies:

In all formulae containing stereocenters, any stereoconfiguration may bepresent, unless indicated otherwise. If a compound is the product of aprocess according to the present invention, those stereocenters of thestarting material which are not taking part in the reaction willmaintain their stereoconfiguration. In certain embodiments, thestereoconfiguration is as described in the Definitions section above.

In all formulae containing X^(n−), X^(n−) may be an inorganic or organicanion wherein n is 1, 2, or 3, preferably is 1 or 2, and more preferablyis 2.

X^(n−) may be any anion of a known opioid salt, including, but notlimited to, bromide, chloride, iodide, lactate, nitrate, acetate,tartrate, valerate, citrate, salicylate, meconate, barbiturate, HSO₄ ⁻,SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻,PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof.

Preferably, X^(n−) is selected from the group consisting of Cl⁻, HSO₄ ⁻,SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻,PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof. More preferably,X^(n−) is HSO₄ ⁻, SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate,or a mixture thereof. Even more preferably, X^(n−) is HSO₄ ⁻, SO₄ ²⁻,methanesulfonate or trifluoroacetate. Even more preferably, X^(n−) isHSO₄ ⁻, SO₄ ²⁻, or trifluoroacetate. Even more preferably, X^(n−) isHSO₄ ⁻ or SO₄ ²⁻. Most preferably, X^(n−) is SO₄ ²⁻.

X^(n−) may be polymer-supported if n is 2 or 3.

Oripavine may be contained in a concentrate of a poppy straw comprisingoripavine as a main alkaloid (CPS-O), or it may be purified oripavine,oripavine obtained from a botanical source, synthetic oripavine,semi-synthetic oripavine, oripavine bioengineered by, e.g., bacteria orplant cell cultures, or a combination of two or more of any of theforegoing.

The 14-hydroxymorphinone salt is preferably

or a solvate (e.g., a hydrate) thereof, respectively. As alreadymentioned above, this compound will in the context of the presentinvention be designated as 14-hydroxymorphinone sulfate. Because of itsstoichiometric composition, it may also be designated asbis(14-hydroxymorphinone)sulfate. The terms 14-hydroxymorphinone sulfateand bis(14-hydroxymorphinone)sulfate are used interchangeably in thecontext of the present invention.

When a solvate of a 14-hydroxymorphinone salt is addressed, it may beany association product of a 14-hydroxymorphinone salt with a solventmolecule. The molar ratio of solvent molecule(s) per molecule of14-hydroxymorphinone salt may vary. The molar ratio of solvent tocompound/salt in the solvate may be 1 (e.g., in a monohydrate), morethan 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), or less than 1 (e.g.,0.5 in a hemihydrate). The molar ratio need not be an integer ratio, itcan also be, e.g., 0.5 (as in a hemihydrate) or 2.5. For example, 1molecule water per molecule of 14-hydroxymorphinone sulfate is bound in14-hydroxymorphinone sulfate monohydrate. The solvate of the14-hydroxymorphinone salt is in certain embodiments a hydrate, forexample a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrateor hexahydrate, or a hydrate wherein the ratio of water per molecule isnot necessarily an integer, but within the range of from 0.5 to 10.0. Incertain embodiments, the solvate of the 14-hydroxymorphinone salt is ahydrate wherein the ratio of water per molecule is within the range offrom 1 to 8. In certain embodiments, the solvate of the14-hydroxymorphinone salt is a hydrate wherein the ratio of water permolecule is within the range of from 1 to 6, i.e. a mono- tohexahydrate. In certain embodiments, the solvate of the14-hydroxymorphinone salt is a monohydrate or a pentahydrate. The sameapplies to other solvates in the context of the present invention, e.g.solvates of oxymorphone or of a salt thereof.

II. Processes for Preparation of Oxymorphone or (PharmaceuticallyAcceptable) Salts or Solvates Thereof by Hydrogenation in the Presenceof Trifluoroacetic Acid and/or Glycol

The present invention provides a process for preparing oxymorphone or an(optionally pharmaceutically acceptable) salt or solvate thereof from a14-hydroxymorphinone salt or a solvate thereof as represented in thefollowing Scheme 10:

the process comprising or consisting of the steps of

-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol, preferably    trifluoroacetic acid and a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to the oxymorphone,    wherein X^(n−) and n are defined as above.

In certain embodiments, the solution or suspension comprising the14-hydroxymorphinone salt or the solvate thereof is provided in step (a)by performing steps (a) to (b) of the process described in Section II ofPCT/IB2013/001541, steps (a) to (c) of the process described in SectionII of PCT/IB2013/001541, or steps (a) to (d) of the process described inSection II of PCT/IB2013/001541 (said steps (a) to (d) of the processdescribed in Section II of PCT/IB2013/001541 correspond to steps (aa) to(dd) described herein below). When steps (a) to (d) described in SectionII of PCT/IB2013/001541 are performed, the 14-hydroxymorphinone salt orsolvate thereof isolated in step (d) thereof is dissolved or suspendedto provide the solution or suspension of said compound in step (a) ofthe process according to the present invention.

In certain embodiments, the solution or suspension comprising the14-hydroxymorphinone salt or the solvate thereof is the compositiondescribed in Section IV-A of PCT/IB2013/001541.

The hydrogenation of step (c) may be hydrogenation with H₂ or transferhydrogenation. Typically, the hydrogenation is performed in the presenceof a hydrogenation catalyst. Preferably, the hydrogenation is performedwith H₂ and a hydrogenation catalyst.

An exemplary hydrogenation reaction is depicted in Scheme 11:

Scheme 11 takes into account that 8-hydroxyoxymorphone or a salt thereofmay be present in the starting material in addition to14-hydroxymorphinone sulfate (or any other 14-hydroxymorphinone salt).Said 8-hydroxy compound may carry over during the hydrogenationreaction. Or, as the hydrogenation is performed under acidic conditions,said 8-hydroxy compound may be converted partially or completely to thecorresponding 14-hydroxy compound 14-hydroxymorphinone during thehydrogenation reaction. Thus, 14-hydroxymorphinone and8-hydroxyoxymorphone may be present in the reaction product whichcontains oxymorphone as main hydrogenation product. However, typically,neither 8-hydroxyoxymorphone nor 14-hydroxymorphinone are present in thefinal oxymorphone when the preferred embodiments of the hydrogenationreaction of the present invention are performed.

In the context of the present invention, it is also considered toprecipitate and isolate the oxymorphone as its free base. Theprecipitation and isolation of the free base of the oxymorphone canresult in a further purification effect, as the precipitated base maycontain less 8-hydroxyoxymorphone and/or 14-hydroxymorphinone than themother liquor. In particular, 8-hydroxymorphone can be removed byprecipitation because its majority remains in the supernatant whenoxymorphone is precipitated as its free base.

As the hydrogenation is performed under acidic conditions, theby-products present in the starting material and in the product may bepresent in their protonated form, or as a salt or solvate thereof.

The amount of TFA added in step (b) may be in the range from 5 to 99 mol% as compared to the molar amount of 14-hydroxymorphinone contained inthe starting material. Preferably, TFA is used in a substoichiometricamount, that is, less TFA is added (in mol) than 14-hydroxymorphinone(in mol) which is contained in the starting material. Thus, it ispreferred that the amount of TFA added in step (b) is 99 mol % or less(0.99 equivalents or less), more preferably from 10 to 70 mol % (0.1 to0.7 equivalents), even more preferably from 30 to 50 mol % (0.3 to 0.5equivalents), even more preferably from 35 to 45 mol % (0.35 to 0.45equivalents) as compared to the molar amount of 14-hydroxymorphinonecontained in the starting material. Thus, the amount of TFA, and thetotal amount of acid in the reaction mixture is lower than inconventional hydrogenation reactions leading from 14-hydroxymorphinoneto oxymorphone, resulting in the advantages described under Summary ofthe Invention in connection with the substoichiometric amount of TFA.

The amount of glycol added in step (b) is typically in the range from 1to 8 volumes/weight (vol/w), preferably from 1.5 to 5 vol/w, morepreferably from 2 to 3 vol/w, calculated for the glycol volume in mL inrelation to the weight in g of 14-hydroxymorphinone salt (for example,in Example 16, 23 g 14-hydroxymorphinone sulfate and 60 mL of propyleneglycol are used, resulting in 2.61 vol/w propylene glycol).

Preferably, the glycol is selected from the group consisting of ethyleneglycol, propylene glycol, 1,3-propanediol, 1,2-butanediol,1,3-butanediol, neopentylglycol, and mixtures thereof. More preferably,the glycol is ethylene glycol, propylene glycol, or a mixture thereof.

A combination of TFA with glycol is especially preferred. In saidcombination, the glycol is preferably selected from the group consistingof ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol,1,3-butanediol, neopentylglycol, and mixtures thereof. More preferably,the glycol is ethylene glycol, propylene glycol, or a mixture thereof.In said combination, the volume ratio of TFA to glycol is preferablyfrom 1:15 to 1:45 (vol/vol), more preferably from 1:20 to 1:40(vol/vol), and even more preferably from 1:25 to 1:35 (vol/vol). Aparticular embodiment is an embodiment where said ratio is about 1:30(vol/vol).

The hydrogenation is generally performed at a temperature of from about25° C. to about 85° C., preferably from about 25° C. to about 60° C.,more preferably from about 25° C. to about 50° C., more preferably fromabout 25° C. to about 45° C., more preferably from about 25° C. to about40° C., and even more preferably from about 28° C. to about 36° C.(e.g., at 30° C. as in Examples 16 and 17).

Preferably, the hydrogenation is performed with hydrogen gas.

The hydrogenation using hydrogen gas is performed at a suitablepressure. In certain embodiments, the hydrogenation is performed at apressure of from about ambient pressure (about 14.7 psia, 101.35 kPa) toabout 100 psia (689.48 kPa). In certain embodiments, it is performed ata pressure of from about 35 psia (241.32 kPa) to about 80 psia (551.58kPa), e.g., at about 60 psia (413.69 kPa). In preferred embodiments, itis performed at a pressure of from about 14.7 psia (101.35 kPa) to about60 psia (413.69 kPa).

The hydrogenation reaction may be run from about 0.5 minute to about 48hours, from about 1 minute to about 42 hours, from about 2 minutes toabout 26 hours, from about 1 minute to about 24 hours, from about 3minutes to about 22 hours, from about 4 minutes to about 20 hours, fromabout 5 minutes to about 18 hours, from about 7 minutes to about 16hours, from about 10 minutes to about 12 hours, from about 12 minutes toabout 12 hours, from about 20 minutes to about 12 hours, from about 30minutes to about 4 hours, from about 2 hours to about 6 hours, or fromabout 3 hours to about 6 hours. In certain embodiments, thehydrogenation reaction is run from about 1 hour to about 48 hours.

In certain embodiments, the hydrogenation reaction is run for about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours,about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5hours, about 5.5 hours, or about 6 hours.

In certain embodiments, the hydrogenation reaction is run for about 8hours, about 12 hours, about 16 hours, about 20 hours, or about 24hours.

In certain embodiments, the hydrogenation reaction is run for about 26hours, about 30 hours, about 34 hours, about 38 hours, about 42 hours,or about 48 hours.

Generally, the hydrogenation reaction is run until completion, i.e.until 14-hydroxymorphinone has disappeared from the reaction mixture.This can be monitored by any suitable detection method, e.g. by the HPLCmethods described herein, in particular the HPLC method of Example 11B.

An exemplary non-limiting list of hydrogenation catalysts includes,e.g., Pd/C, palladium-charcoal, a combination of diphenylsilane andPd/C, Pd(Ph₃P)/ZnCl₂, a combination of Pd/C with sodium hypophosphite(e.g., in aqueous trifluoroacetic acid), Pt/C, Ru/C, Rh/C, PdO₂, PtO₂,zinc, magnesium. In certain embodiments, the catalyst is a palladiumcatalyst. Preferably, the catalyst is Pd/C, in particular Pd/C with 5%Pd.

In certain embodiments, the hydrogenation catalyst is not a metal, e.g.,when the hydrogenation is a metal-free transfer hydrogenation asdescribed in Yang, J. W. et al., Angew. Chem. Int. Ed. (2004)43:6660-6662.

In certain embodiments, a solid support catalyst is used, e.g., toensure reaction completion upon contact and/or potentially prevent orminimize the formation of any new 14-hydroxymorphinone from8-hydroxyoxymorphone.

Transfer hydrogenation involves the use of a hydrogen transfer reagent.

Suitable hydrogen transfer reagents include HCO₂H, HCO₂H/HCO₂Na,HCO₂H/NEt₃, HCHO, H₂SO₄, HCO₂Na/NEt₃, H₂SO₄/NEt₃, H₃CSO₂NHNH₂/NEt₃, acombination thereof, and the like. Other hydrogen donors, likeisopropanol, indoline, cyclohexene, sodium borohydride,tetrahydroquinoline, 2,5-dihydrofuran, phosphoric acid, sodiumdithionite, and combinations thereof, might also be useful. In certainembodiments, the hydrogen transfer reagent is a dihydropyridine, e.g.,as described in Yang, J. W. et al., Angew. Chem. Int. Ed. (2004)43:6660-6662.

The hydrogenation may be done by a batch method or in a continuouslyflowing stream.

In certain embodiments, the hydrogenation is done by a batch method. Inan exemplary batch method, a catalyst (e.g., palladium on carbon) ischarged into a batch reactor. A solution or suspension of the14-hydroxymorphinone salt or the solvate thereof is added, or the14-hydroxymorphinone salt and the solvent are added separately.Trifluoroacetic acid and/or glycol are added. If necessary, water isalso added. The batch reactor is then sealed and hydrogenated (e.g., at14.7 psia (101.35 kPa), and 30° C.) for a time period sufficient tocomplete hydrogenation (e.g., for 48 hours). The catalyst is thenremoved by filtration.

The resulting oxymorphone may then be precipitated as its free base byaddition of a base, e.g., of sodium hydroxide or ammonium hydroxide.Preferably, sodium hydroxide is used, because the resulting precipitateshows a better behavior in subsequent reactions. The precipitation maybe enhanced by adding an antisolvent. The precipitated solids are thenoptionally washed and dried. The precipitation step (d) is described inmore detail below.

In certain embodiments, the hydrogenation reaction is conducted in acontinuously flowing stream. A reaction in a continuously flowing streamof the reactants allows for the transport of matter into and out of thereaction mixture as the reaction is taking place. Running the reactionin a continuously flowing stream allows, e.g., better control overreaction conditions (including, e.g., time, temperature, equivalents ofreagents, pressure, temperature, time of exposure of reactants tocatalysts, pH, etc.), and isolation and/or removal of the oxymorphonefrom the reaction mixture as it is being formed and/or before anyundesired compound is formed. In certain embodiments, the oxymorphone isremoved from the reaction mixture as it is being formed.

In certain embodiments, conducting the reaction in a continuouslyflowing stream allows for conducting the reaction at a temperature whichexceeds the boiling point of the solvent, because the pressure can besafely maintained.

In certain embodiments, conducting the reaction in a continuouslyflowing stream increases the yield of the reaction, increases the volumeefficiency of the reaction and/or decreases the number and amounts ofby-products formed during the hydrogenation reaction, as the oxymorphoneis removed before it reacts with and/or is degraded by the remainingreactants.

The 14-hydroxymorphinone salt or solvate thereof is taken up in asuitable solvent in step (a) of the process according to the presentinvention. Thus, a suspension or solution of the 14-hydroxymorphinonesalt is formed. The hydrogenation product formed during the processtypically dissolves in the solvent. In certain embodiments, the solutionor suspension of step (a) is provided by using the glycol of step (b) assolvent. In said embodiments, the glycol is either the sole solvent, orit is mixed with other suitable solvents. In particular, it ispreferably mixed with water, because water is advantageous if the pHshall be raised after the hydrogenation is complete in order to isolatethe oxymorphone as its free base. Preferably, said glycol is selectedfrom the group consisting of ethylene glycol, propylene glycol,1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol, andmixtures thereof. More preferably, the glycol is ethylene glycol,propylene glycol, or a mixture thereof. Other suitable solvents for theprocess according to the present invention include or consist of, e.g.,methanol, tetrahydrofuran, isopropanol, acetone, ethanol,1-methoxy-2-propanol, 2-ethoxyethanol, tert-amyl alcohol, isobutanol,2-methyl-tetrahydrofuran, n-propanol, 1-butanol, 2-butanol,tert-butanol, isopropyl acetate, and di(ethylene glycol) or a mixture ofwater with any one of the foregoing, or consist of water; preferably,the other suitable solvents include or consist of methanol,tetrahydrofuran, isopropanol, acetone, ethanol, 1-methoxy-2-propanol,2-ethoxyethanol, tert-amyl alcohol, or a mixture of water with any oneof the foregoing, or consist of water.

Water or a mixture of water with any of the foregoing solvents, inparticular with the foregoing glycol, is preferred.

In certain embodiments, the suitable solvent is a 20:80 ethyleneglycol:water mixture, 30:70 ethylene glycol:water mixture, 40:60ethylene glycol:water mixture, 50:50 ethylene glycol:water mixture,60:40 ethylene glycol:water mixture, 70:30 ethylene glycol:watermixture, 80:20 ethylene glycol:water mixture, 90:10 ethyleneglycol:water mixture, 100:0 ethylene glycol:water mixture, a 20:80propylene glycol:water mixture, 30:70 propylene glycol:water mixture,40:60 propylene glycol:water mixture, 50:50 propylene glycol:watermixture, 60:40 propylene glycol:water mixture, 70:30 propyleneglycol:water mixture, 80:20 propylene glycol:water mixture, 90:10propylene glycol:water mixture, 100:0 propylene glycol:water mixture, a50:50 methanol:water mixture, 60:40 methanol:water mixture, 70:30methanol:water mixture, 80:20 methanol:water mixture, 90:10methanol:water mixture, 100:0 methanol:water mixture, 50:50ethanol:water mixture, 60:40 ethanol:water mixture, 70:30 ethanol:watermixture, 80:20 ethanol:water mixture, 90:10 ethanol:water mixture, 100:0ethanol:water mixture, 90:10 tetrahydrofuran:water mixture, 100:0tetrahydrofuran:water mixture, 90:10 isopropanol:water mixture, 70:30acetone:water mixture, 80:20 acetone:water, or 90:10 acetone:watermixture. 8-Hydroxyoxymorphone is more soluble in these mixtures thanoxymorphone base and therefore may remain in solution while theoxymorphone free base may be precipitated by addition of a base at theend of the hydrogenation.

In certain preferred embodiments, the suitable solvent comprises orconsists of a mixture of glycol and water. Preferably, said glycol isselected from the group consisting of ethylene glycol, propylene glycol,1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol, andmixtures thereof. More preferably, the glycol is ethylene glycol,propylene glycol, or a mixture thereof.

In certain embodiments, the suitable solvent comprises or consists of amixture of ethylene glycol and water.

In certain embodiments, the suitable solvent comprises or consists of amixture of propylene glycol and water.

It is preferable to have more water than glycol in the hydrogenationreaction mixture. I.e., a glycol:water mixture containing less than 50parts glycol per 50 parts of water is preferred. Preferred mixtures are30:70 glycol:water mixtures, 35:65 glycol:water mixtures, 40:60glycol:water mixtures, and 45:55 glycol:water mixtures, and ratiosbetween these ratios, The preferred range is from 20:80 to less than50:50 glycol:water mixtures, more preferably from 30:70 to 45:55glycol:water mixtures, and more preferably from 35:65 to 45:55glycol:water mixtures. In particular, mixtures of about 40:60glycol:water are preferred. Especially preferred are mixtures of from35:65 to 45:55, preferably about 40:60 ethylene glycol:water, or of from35:65 to 45:55, preferably about 40:60 propylene glycol:water.

In certain embodiments, the suitable solvent used in step (a) comprisesor consists of water and the glycol is added in step (b). In certainother embodiments, both glycol and water are added simultaneously(either separately or as mixture) to the reaction mixture at thebeginning of the hydrogenation process; in said embodiments, thesolution or suspension of step (a) is provided by using the glycol ofstep (b) as solvent.

Once the hydrogenation is completed, the oxymorphone may be precipitatedas its free base or a salt or solvate thereof.

In certain embodiments, the oxymorphone is precipitated as its salt or asolvate thereof. In said salt, the anion may be trifluoroacetate, or thesame X^(n−) as in the starting material 14-hydroxymorphinone salt, or amixture thereof.

Preferably, the oxymorphone is precipitated as its free base, inparticular by step (d):

-   (d) adding a base, thus raising the pH to a pH where the oxymorphone    precipitates, and isolating the oxymorphone as its free base or a    solvate thereof.

Said step (d) is combined with steps (a) to (c) in a preferred processaccording to the present invention, and said preferred process eithercomprises steps (a) to (d) or consists of steps (a) to (d). Withoutbeing bound by theory, it is assumed that the combination of theprecipitation and isolation step (d) with the hydrogenation reaction ofsteps (a) to (c) gives the best results, i.e. results in the lowestamount of 8-hydroxyoxymorphone and 14-hydroxymorphinone in the finaloxymorphone base.

The pH where the oxymorphone precipitates can be determined by routinemeasures. However, it is generally in the range from 8.5 to 9.2,preferably at about 9.0.

The base added in step (d) may be any Bronsted base, provided that itscomponents do not form an insoluble salt with other components of thereaction mixture. The base is preferably selected from the groupconsisting of NaOH, KOH, Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, HCO₂Na, CH₃CO₂Na,NEt₃, NH₄OH or any mixtures thereof. More preferably, it is a basecontaining hydroxide as anion, even more preferably it is an alkalihydroxide or pseudo-alkali hydroxide. Even more preferably, it isammonium hydroxide or sodium hydroxide, and most preferably it is sodiumhydroxide. Sodium hydroxide is preferably used, because the resultingprecipitate shows a better behavior in subsequent reactions than theprecipitate resulting from ammonium hydroxide. Ammonium hydroxide formsammonium sulfate or ammonium trifluoroacetate salts that mightprecipitate with the oxymorphone base. These ammonium salts caninterfere, e.g., with the conversion of oxymorphone to naloxone. It isbelieved that they react with N-demethylation agents. The productresulting from sodium hydroxide has less impact on further conversionsof oxymorphone base.

The amount of base added in step (d) has to be sufficient to achieveprecipitation of the oxymorphone in its free base form. Thus, it ispreferably in the range from 0.5 to 2.0 molar equivalents, morepreferably from 0.8 to 1.7 equivalents, even more preferably from 1.1 to1.4 molar equivalents relative to the oxymorphone base. From 1.2 to 1.3molar equivalents base are particularly preferred. Preferably, said baseis sodium hydroxide.

In certain embodiments, the precipitation of the oxymorphone or salt orsolvate thereof is enhanced by one or more of the following:

-   (i) adjusting (e.g., lowering) the temperature of the reaction    mixture to the precipitation temperature;-   (ii) addition of an antisolvent;-   (iii) addition of a seed crystal;-   (iv) changing the ionic strength of the reaction mixture (e.g., by    addition of a salt);-   (v) concentrating the reaction mixture;-   (vi) reducing or stopping agitation of the reaction mixture;    or any other conventional method for initiating or enhancing    precipitation or crystallization.

When the temperature is adjusted to the precipitation temperature, thismeans that the precipitation of the oxymorphone base or salt or solvatethereof is initiated and/or enhanced by adjusting the temperature of thereaction mixture to or beyond a temperature at which said compoundprecipitates (“precipitation temperature”). The temperature is eitheradjusted by performing the reaction at the precipitation temperature, orby lowering the temperature of the reaction mixture during the reactionor after completion of the reaction.

In certain embodiments, the reaction mixture is adjusted to atemperature of ≤40° C. to initiate precipitation, i.e. the precipitationtemperature is ≤40° C. In certain embodiments, the precipitation isinitiated at a precipitation temperature of about −20° C., about −15°C., about −10° C., about −5° C., about 0° C., about 5° C., about 10° C.,about 15° C., about 17° C., about 19° C., about 21° C., about 23° C.,about 25° C., about 27° C., about 29° C., about 31° C., about 33° C.,about 35° C., about 37° C., or about 40° C.

In certain embodiments, the precipitation temperature is in a range offrom about −20° C. to about 40° C., preferably from about −10° C. toabout 40° C., more preferably from about −5° C. to about 35° C.

In certain embodiments, the precipitation temperature is in a range offrom about −10° C. to about 22° C., preferably from about −5° C. toabout 10° C., more preferably from about −5° C. to about 5° C.

In certain embodiments, an antisolvent is used in addition to adjustingthe temperature to the precipitation temperature. Generally, however,precipitation will also occur without adding an antisolvent.

Precipitation may also be achieved or enhanced by adding an antisolventto a solution of the oxymorphone or oxymorphone salt, or by preparing asupersaturated solution (e.g. by cooling or concentrating a reactionmixture) from which the resulting oxymorphone or salt or solvate thereofis precipitated, e.g. by cooling beyond the precipitation temperature orby adding a seed crystal. The precipitated solids are then optionallywashed and dried. In one aspect, this precipitation may be achieved byadding one or more of acetone, 1-methoxy-2-propanol, 2-butanol, andtert-butyl methyl ether to a reaction mixture. In a specific embodiment,tert-butyl methyl ether is added to a reaction mixture which already maycomprise water (which may be the sole solvent in the reaction mixture).In another specific embodiment, 2-butanol is added to a reaction mixturewhich already may comprise water. In one aspect, this precipitation maybe achieved by using a mixture of water and an antisolvent, inparticular a mixture of water, or a mixture of water and tert-butylmethyl ether, or a mixture of water, tetrahydrofuran, and tert-butylmethyl ether. Said mixture may replace the reaction solvent aftercompletion of the hydrogenation reaction. The mixture can also beprepared by adding antisolvent after completion of the hydrogenationreaction. 2-Butanol is the most preferred antisolvent.

Further suitable antisolvents may be the antisolvents described inSection IV. I.e., a suitable antisolvent may comprise or consist oftert-butyl methyl ether, diethyl ether, hexane(s), tert-amyl alcohol,methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol,tert-butanol, isobutanol, heptanes, xylenes, toluene, acetone,2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran,2-methyl-tetrahydrofuran, 1,2-dichloroethane, chloroform,dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol, 1,4-dioxane,methyl formate, methyl acetate, or a mixture of two or more of any ofthe foregoing. The listed alcohols and ethers are the preferredantisolvents, the alcohols being even more preferred. In some preferredembodiments, the antisolvent is isopropanol or 2-butanol. The mostpreferred antisolvent is 2-butanol.

The resulting precipitate may then be isolated, thus removing it fromthe mother liquor and advantageously further purifying the free basefrom 8-hydroxyoxymorphone and/or 14-hydroxymorphinone which remains inthe mother liquor.

Preferably, the oxymorphone is isolated as its free base. The resultingoxymorphone in its form as free base comprises lower amounts of8-hydroxyoxymorphone and/or 14-hydroxymorphinone (or salt or solvatethereof) as compared to oxymorphone made by a process which does notinvolve the hydrogenation according to the present invention.

Oxymorphone and compositions comprising said oxymorphone which can beprepared via the process of present invention are described, e.g., inSection VI below. The amounts of 8-hydroxyoxymorphone and14-hydroxymorphinone which may be present in the compositions comprisingthe oxymorphone are described in Section VI below. In certainembodiments, this oxymorphone or these compositions comprising theoxymorphone are the product of the process described in the presentsection or in the subsequent Section III.

In certain embodiments, the compositions comprising the oxymorphonewhich are the product of the process described in the present section orin the subsequent Section III can be used as pharmaceutical compositionswithout further processing or purification steps, in particular withoutfurther hydrogenation steps.

In certain embodiments of this process, the 14-hydroxymorphinone salt is14-hydroxymorphinone sulfate or a solvate thereof.

In certain embodiments of this process, the 14-hydroxymorphinone salt is14-hydroxymorphinone trifluoroacetate or a solvate thereof.

III. Processes for Preparing Oxymorphone Starting from Oripavine

Present invention further provides a process for preparing oxymorphonefrom oripavine via a 14-hydroxymorphinone salt or a solvate thereof. Inthis process, the 14-hydroxymorphinone salt or solvate thereof serves asan intermediate. Said intermediate 14-hydroxymorphinone salt or thesolvate thereof may either be isolated or converted to oxymorphone or asalt or solvate thereof without further isolation. In certain preferredembodiments, said intermediate 14-hydroxymorphinone salt or the solvatethereof is isolated before its conversion to the oxymorphone or a saltor solvate thereof.

Thus, present invention provides a process for preparing oxymorphone ora salt or solvate thereof from oripavine or a salt or solvate thereof,the process comprising or consisting of (Scheme 12):

-   (aa) oxidizing the oripavine to 14-hydroxymorphinone;-   (bb) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before,    during and/or after the oxidation reaction;-   (cc) optionally precipitating the resulting 14-hydroxymorphinone as    14-hydroxymorphinone salt or a solvate thereof;-   (dd) optionally isolating the precipitated 14-hydroxymorphinone salt    or solvate thereof;-   (a) providing a solution or suspension of the 14-hydroxymorphinone    salt or a solvate thereof;-   (b) adding trifluoroacetic acid and/or a glycol, preferably    trifluoroacetic acid and a glycol; and-   (c) hydrogenating the resulting mixture, thus reducing the    14-hydroxymorphinone to oxymorphone,    wherein X^(n−) and n are defined as above.

In certain embodiments, the 14-hydroxymorphinone salt or solvate thereofis precipitated and/or isolated in steps (cc) and/or (dd) before thehydrogenation via steps (a) to (c).

In certain embodiments, said process will contain a further step, namely(d) adding a base, thus raising the pH to a pH where the oxymorphoneprecipitates, and isolating the oxymorphone as its free base or asolvate thereof. See above, Section II.

In certain embodiments, step (c) of the process results in apharmaceutically acceptable salt or solvate of the oxymorphone. Incertain embodiments, step (c) of the process results not only in suchpharmaceutically acceptable salt or solvate of the oxymorphone, but thecomplete resulting composition can be used as pharmaceutical compositionwithout requiring further processing (e.g., purification). Inparticular, it may be used without an additional hydrogenation to removeby-products, e.g., 14-hydroxymorphinone. For example, the process mayresult in an oxymorphone salt composition which is suitable forincorporation into a dosage form, the oxymorphone salt composition beingdirectly prepared from the hydrogenation product of step (c) by aconversion which does not include a further/additional hydrogenationstep.

In certain embodiments, the salt or solvate of oxymorphone which resultsfrom step (c) is not a pharmaceutically acceptable salt or solvate.

In certain embodiments, the oxymorphone or salt or solvate thereofresulting from step (c) may be converted into a pharmaceuticallyacceptable salt or solvate thereof in an additional step at the end ofthe process. Methods for such conversion are known in the art (e.g.,anion exchange).

In certain embodiments, the 14-hydroxymorphinone salt or solvate thereofwhich is an intermediate of the process will have the properties asdescribed in Section IV of PCT/IB2013/001541.

All elements of steps (a) to (d) of said process and the embodiments ofsaid elements have already been described above. All elements of steps(aa) to (dd) of said process and the embodiments of said elements havealready been described in PCT/IB2013/001541 (as steps (a) to (d) inSection II of PCT/IB2013/001541). Oxymorphone which can be prepared viathe process, and the amounts of 8-hydroxyoxymorphone and14-hydroxymorphinone which may be present in compositions comprisingsaid oxymorphone are described in Section VI below. In certainembodiments, these compounds are the product of the process described inthe present section.

In the following, an exemplary embodiment of said process will bedescribed. Therein the starting compound for the oxidation reaction isoripavine or a salt or solvate thereof,

-   the oxidation agent comprises or is performic acid formed in situ    from hydrogen peroxide and formic acid, the acid H⁺ _(n)X^(n−) in    step (bb) is sulfuric acid which is added to the reaction mixture,-   the 14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate or a    solvate thereof, and the product is oxymorphone or a salt or solvate    thereof.

In a preferred embodiment, the oxymorphone is precipitated and isolatedas its free base.

IV. Processes for Preparing a 14-Hydroxymorphinone Salt

A 14-hydroxymorphinone salt, the starting material for the processaccording to the present invention, can be prepared according to theprocesses for preparing a compound of formula V described in Section IIof PCT/IB2013/001541. The contents of this Section II ofPCT/IB2013/001541 are explicitly incorporated herein by reference.

Hence, in certain embodiments, the 14-hydroxymorphinone salt or asolvate thereof

can be prepared from oripavine or a salt or solvate thereof, the processcomprising:

-   (aa) oxidizing the oripavine to 14-hydroxymorphinone; and-   (bb) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before,    during and/or after the oxidation reaction, wherein    X^(n−) and n are defined as above.

In a preferred embodiment, the acid H⁺ _(n)X^(n−) is added to thereaction mixture before or during the oxidation reaction. Morepreferably, the acid H⁺ _(n)X^(n−) is present in the reaction mixtureduring the complete oxidation reaction, i.e. it is added before thestart of the oxidation reaction, or at the start of the oxidationreaction.

In addition to the 14-hydroxymorphinone salt, the oxidation of oripavinemay generate 8-hydroxyoxymorphone or a salt or solvate thereof. The8-hydroxyoxymorphone may be formed as follows:

The use of the 14-hydroxymorphinone salt or solvate thereof as startingmaterial in the hydrogenation process of the present invention canreduce the amount of the 8-hydroxyoxymorphone which is present at thebeginning of the hydrogenation, as compared to a process for preparationof oxymorphone without involving the 14-hydroxymorphinone salt.

The formation of a 14-hydroxymorphinone salt and the isolation of theprecipitated salt appear to prevent or reduce (i) the formation of8-hydroxyoxymorphone during oxidation of oripavine, as compared toprocesses which do not involve the formation of the 14-hydroxymorphinonesalt, (ii) the presence of 8-hydroxyoxymorphone in a compositioncomprising oxymorphone base made via a 14-hydroxymorphinone salt, and(iii) the presence of 8-hydroxyoxymorphone or a salt thereof and14-hydroxymorphinone or a salt thereof in an oxymorphone salt or in apharmaceutical composition comprising an oxymorphone salt made via a14-hydroxymorphinone salt.

Pharmaceutical compositions prepared by processes of the presentinvention may be quantitatively different from pharmaceuticalcompositions prepared by conventional processes which do not utilize thehydrogenation reaction conditions of the present invention, and mayoffer advantages over the compositions prepared by conventionalprocesses, e.g., in terms of safety, efficiency and reducedmanufacturing costs. For example, these compositions may contain lessby-products and/or require less or no further processing steps aftersynthesis of their API.

An exemplary embodiment of a process for preparing a14-hydroxymorphinone salt is a process for preparing14-hydroxymorphinone as its sulfate salt (or a solvate thereof), whichencompasses the oxidation of oripavine illustrated in Scheme 13:

In a preferred embodiment of the present invention, the14-hydroxymorphinone salt is

(14-hydroxymorphinone sulfate) or a solvate thereof.

As described above, 8-hydroxyoxymorphone may be converted to14-hydroxymorphinone during further processing of the14-hydroxymorphinone salt to oxymorphone or a salt or solvate thereof.If less 8-hydroxyoxymorphone is formed during the oxidation reaction,less 8-hydroxyoxymorphone and ultimately less 14-hydroxymorphinone mayfinally be present in oxymorphone or an (optionally pharmaceuticallyacceptable) salt or solvate thereof (e.g., oxymorphone hydrochloride)made via or from the 14-hydroxymorphinone salt or a solvate thereof, ascompared to oxymorphone or a salt or solvate thereof made via adifferent intermediate. Less 8-hydroxyoxymorphone and ultimately less14-hydroxymorphinone may then also finally be present in apharmaceutical composition or dosage form containing said oxymorphone ora pharmaceutically acceptable salt or solvate thereof. Ultimately, theuse of the 14-hydroxymorphinone salt as starting material for thehydrogenation process of the present invention may therefore contributeto the result that the amount of 8-hydroxyoxymorphone and14-hydroxymorphinone formed during preparation of oxymorphone or salt orsolvate thereof is insufficient to increase the total amount of the14-hydroxymorphinone in said oxymorphone above an undesired level, e.g.,above a desired threshold amount of 14-hydroxymorphinone.

In certain embodiments, the oxidation step (aa) is partially orcompletely performed in the presence of the acid H⁺ _(n)X^(n−) in thereaction mixture. That is, the acid is added before or during theoxidation reaction, preferably before the oxidation reaction. The acidH⁺ _(n)X^(n−) is preferably present in the reaction mixture during thecomplete oxidation reaction, i.e. it is added before the start of theoxidation reaction, or at the start of the oxidation reaction.

The 14-hydroxymorphinone salt may precipitate in certain embodiments ofthe oxidation reaction.

The formation of the 14-hydroxymorphinone salt or solvate thereof mayoccur via a salt formed from the oripavine, via 14-hydroxymorphinone inits free base form or in its salt or solvate form, via both of saidroutes, or via a combination of one or both of said routes with otherreaction routes known to a person skilled in the art. During thisreaction, at least a part or all of the oripavine and/or14-hydroxymorphinone are protonated. This may happen, e.g., under acidicreaction conditions.

In certain embodiments of the oxidation reaction, the formation of the14-hydroxymorphinone salt or a solvate thereof in this process allowsfor a more volume efficient oxidation of the oripavine in comparison toa process wherein no 14-hydroxymorphinone salt is formed.

In certain embodiments of the oxidation reaction, the formation of the14-hydroxymorphinone salt results in a lower ratio of8-hydroxyoxymorphone to the 14-hydroxymorphinone in the product, ascompared to a process wherein no 14-hydroxymorphinone salt or solvatethereof is formed.

In certain embodiments of the oxidation reaction, said result may beachieved because the formation of the 14-hydroxymorphinone salt or asolvate thereof has the effect that less 8-hydroxy compound is formedduring the oxidation reaction in comparison to an oxidation reactionwhere no 14-hydroxymorphinone salt or solvate thereof is formed. Inother words, the formation of the 14-hydroxymorphinone salt allows foran improvement of the by-product profile of the reaction product.

In these embodiments, the oxidation reaction is typically completely orpartially performed in the presence of the acid H⁺ _(n)X^(n−).

One example for such embodiment may be the formation of a14-hydroxymorphinone salt, wherein n is 2 and preferably wherein X^(n−)is sulfate. Another example for such embodiment may be the formation ofa 14-hydroxymorphinone salt, wherein n is 1 and preferably whereinX^(n−) is trifluoroacetate. Another example for such embodiment may bethe formation of a 14-hydroxymorphinone salt, wherein n is 3 andpreferably wherein X⁻ is phosphate.

In certain embodiments of the oxidation reaction said result may beachieved because the formation of the 14-hydroxymorphinone salt or asolvate thereof has the effect that 8-hydroxyoxymorphone can beseparated from the 14-hydroxymorphinone salt or the solvate thereof,e.g., by precipitation of the 14-hydroxymorphinone salt or the solvatethereof from the reaction mixture. One example for such an embodimentmay be the formation of a 14-hydroxymorphinone salt wherein X^(n−) issulfate.

In certain embodiments a combination of these effects takes place, i.e.,said result is achieved because both less 8-hydroxyoxymorphone is formedduring the oxidation and because said compound can be separated from the14-hydroxymorphinone salt or solvate thereof. One example for such anembodiment may be the formation of a 14-hydroxymorphinone salt whereinX^(n−) is sulfate.

Preferably, the formation of the 14-hydroxymorphinone salt or a solvatethereof reduces the formation of 8-hydroxy compounds during theoxidation reaction and/or the presence of 8-hydroxy compounds in theoxidation product, as compared to an oxidation reaction which does notinvolve the step of forming the 14-hydroxymorphinone salt or a solvatethereof. The presence of 8-hydroxyoxymorphone in the product may bereduced by precipitation of the 14-hydroxymorphinone salt. This mayreduce the formation of 14-hydroxymorphinone during subsequent reactions(e.g., during conversion of oxymorphone made from a 14-hydroxymorphinonesalt to oxymorphone hydrochloride), as compared to reactions which donot involve the step of forming the 14-hydroxymorphinone salt or asolvate thereof.

The process for preparing the 14-hydroxymorphinone salt or a solvatethereof may be performed by oxidizing oripavine with an oxidizing agentin the presence of one or more acids such that the 14-hydroxymorphinonesalt is formed. An 8-hydroxy compound or a salt or solvate thereof maybe formed as by-product during the oxidation. At the end of thepreparation of the 14-hydroxymorphinone salt or a solvate thereof, said14-hydroxymorphinone salt or solvate thereof may be provided as a solid,a solution, or a suspension. The 14-hydroxymorphinone salt or a solvatethereof is the starting material or intermediate for the hydrogenationprocess of the present invention, i.e., the process for preparingoxymorphone or an (optionally pharmaceutically acceptable) salt orsolvate thereof. The 14-hydroxymorphinone salt and the solvate thereofwill be described in more detail below. However, the subsequentdescription of the oxidation process shall also apply to the14-hydroxymorphinone salt and the solvate thereof per se whereapplicable (e.g., when the 14-hydroxymorphinone salt is described as areaction product of such oxidation process).

The process step for preparing said 14-hydroxymorphinone salt isdepicted in the following Scheme 14:

In certain embodiments of this process, the acid H⁺ _(n)X^(n−) issulfuric acid.

The process for preparing a 14-hydroxymorphinone salt may be performedas one-pot-reaction, wherein steps (aa) and (bb) are performedconcomitantly. In said one-pot-reaction, at least a part of the acid H⁺_(n)X^(n−) is typically added before the oxidizing agent, orconcomitantly with the oxidizing agent. In certain embodiments, all ofthe acid H⁺ _(n)X^(n−) is added before the oxidizing agent, orconcomitantly with the oxidizing agent.

An exemplary one-pot reaction for forming a 14-hydroxymorphinone salt,namely 14-hydroxymorphinone sulfate, is depicted in Scheme 15:

In the oxidation reaction depicted in this Scheme, a peracid formed fromhydrogen peroxide and formic acid is used as at least one oxidizingagent, and sulfuric acid is used as the acid H⁺ _(n)X^(n−). It should benoted that it is not excluded that at least part of the sulfuric acidalso forms a peracid in the presence of the hydrogen peroxide, whichperoxide may also take part in the oxidation reaction.

The reaction conditions of steps (aa) and (bb) (e.g., time, temperature,pH, relative proportions of the reagents) will be described in detail inthe following. In a typical embodiment of the present invention, theyare adjusted such that the resulting product containing the14-hydroxymorphinone salt is free from, or contains about 2500 ppm orless, about 2000 ppm or less, about 1500 ppm or less, about 1000 ppm orless, about 500 ppm or less, or about 100 ppm or less of8-hydroxyoxymorphone.

Oxidation Reaction

The oxidation reaction of step (aa) of the process is represented inScheme 16 and results in the formation of 14-hydroxymorphinone, which inturn is part of the 14-hydroxymorphinone salt:

The oxidation reaction of step (aa) is generally run until at leastabout 90%, about 92%, about 95%, about 97%, about 98%, about 99% orabout 100% of the oripavine is consumed by the reaction. The amount ofsaid compound remaining in the reaction may be determined by anyconventional determination method, e.g., by HPLC, for example the HPLCmethod described in Example 11A.

The oxidizing reaction time can be anywhere from about 1 minute to about36 hours, from about 10 minutes to about 34 hours, from about 20 minutesto about 32 hours, from about 30 minutes to about 30 hours, from about45 minutes to about 28 hours, from about 1 hour to about 24 hours, fromabout 3 hours to about 21 hours, from about 5 hours to about 18 hours.In certain embodiments, the reaction time is about 30 minutes, about 1hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about24 hours.

The reaction mixture may be maintained at a temperature of from about 0°C. to about 100° C., from about 10° C. to about 90° C., from about 15°C. to about 80° C., from about 20° C. to about 70° C., from about 20° C.to about 60° C., from about 20° C. to about 55° C., from about 20° C. toabout 45° C., from about 20° C. to about 40° C., or from about 20° C. toabout 35° C.

In certain embodiments, e.g., in a reaction conducted in a flow reactor,the reaction mixture may be maintained at a temperature as listed in thepreceding sentence, or it may be maintained at a temperature exceedingsome of the upper temperature limits of the preceding sentence, e.g., ata temperature of from about 40° C. to about 95° C.

In certain embodiments, the reaction mixture is maintained at from about20° C. to about 45° C., preferably from about 25° C. to about 40° C. Incertain embodiments, the reaction mixture is maintained more preferablyat from about 25° C. to about 35° C., even more preferably at about 30°C. In certain especially preferred embodiments, the reaction mixture ismaintained more preferably at from about 30° C. to about 38° C., morepreferably at from about 32° C. to about 36° C., even more preferably atabout 35° C. Typically, the oxidation reaction will be finished afterabout 24 hours or even less hours (e.g., 16 or 20 hours) when thesepreferred temperatures are used.

Typically, the oxidation of the oripavine during step (aa) is takingplace in the presence of an oxidizing agent. Said oxidizing agent iseither added to the reaction mixture, or it is formed in situ in thereaction mixture (e.g., performic acid may be formed in situ in areaction mixture comprising formic acid and hydrogen peroxide). Theoripavine is then oxidized to the 14-hydroxymorphinone salt, which willresult when the acid H⁺ _(n)X^(n−) is present.

The oripavine may be provided for step (aa) in a solution or suspensioncomprising the oripavine and a suitable solvent. A suitable solvent maycomprise or consist of water; an alcohol (e.g., methanol, ethanol,n-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, tert-butanol,tert-amyl alcohol, 2-ethoxyethanol, 1-methoxy-2-propanol, etc.); anaromatic hydrocarbon (e.g., benzene, toluene, xylol, etc.); an ether(e.g., 1,4-dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran,diethylether, tert-butyl methyl ether, etc.); a (C₁-C₄) alkyl ester of a(C₁-C₄) alkanoic acid (e.g., methyl formate, methyl acetate, ethylacetate, isopropyl acetate, etc.); an amide (e.g., dimethylformamide,diethylformamide, dimethylacetamide, or other N—(C₁-C₄) alkylsubstituted (C₁-C₄) alkanoic acid amides); N-methylpyrrolidone;formylmorpholine; or any mixtures of any of the foregoing. In certainembodiments, the reagent providing an acid for the process (e.g., 88%formic acid in water), or the acid itself can act as solvent. In certainembodiments, the solvent comprises or consists of water, an ether, analcohol, or a combination thereof. In certain embodiments, the solventcomprises or consists of methanol, tetrahydrofuran, n-propanol,isopropanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, acetone,ethanol, 1-methoxy-2-propanol, 2-ethoxyethanol, tert-amyl alcohol, or amixture of water with any one of the foregoing. In certain embodiments,the solvent comprises or consists of tetrahydrofuran, isopropanol,methanol, ethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol,tert-amyl alcohol, n-propanol or any combination thereof. In certainembodiments, the solvent is water or a combination of water with anothersolvent. In certain embodiments, the solvent is isopropanol or a mixtureof isopropanol and water. In certain embodiments, the solvent is2-butanol or a mixture of 2-butanol and water. In certain otherembodiments, the solvent is free or substantially free from water (e.g.,when the reaction is performed in chloroform using MCPBA as oxidizingagent). In certain preferred embodiments, the solvent comprises orconsists of water.

The ratio of the oripavine to the solvent is selected such that theoripavine is dissolved in the solvent, i.e. such that a suspension orpreferably a solution of the oripavine is formed. If the oxidizing agentcontains or is generated with an acid which acts as a solvent (e.g.,formic acid), or if the acid H⁺ _(n)X^(n−) acts as a solvent, said acidcontributes to the total amount of solvent in the reaction mixture or isthe sole solvent in the reaction mixture. The ratio of the oripavine (inmmol) to the solvent (in mL) may be defined as molarity by the followingformula:molarity=(mmol of oripavine)/(milliliters of solvent).For example, when 33.7 mmol of oripavine and 23.6 mL water plus formicacid are used, this results in a molarity of 1.43 (33.7/23.6). In thepresent process, the molarity of the oripavine in relation to thesolvent is preferably ≥0.8. In certain embodiments, the molarity is from0.8 to 1.8, preferably from 1.2 to 1.7, more preferably from 1.2 to 1.6and even more preferably from 1.3 to 1.5. In comparison, in WO2008/130553, the molarity is 0.67 ((10 mmol oripavine)/(15 mL water plusformic acid)). The less solvent is used, the more volume efficient steps(aa) and (bb) may be if the process yield remains constant. Thus, thisprocess allows for the use of less solvent, which in turn may reduce theenvironmental burden and/or production costs.

In certain embodiments, the solvent comprises or consists of water, e.g.in the oxidation reactions described in the Examples. The ratio of theoripavine (in mmol) to water (in mL) in said embodiments is preferablyfrom about 1:1 to about 5:1, more preferably from about 1.2:1 to about4:1, more preferably from about 1.5:1 to about 3:1, more preferably fromabout 1.6:1 to about 2.4:1, even more preferably from about 1.7:1 toabout 2.2:1. E.g., in a preferred embodiment, from about 1.5 mL to about2.0 mL, preferably from about 1.6 to about 1.9 mL water per g oripavineare used. This calculation does not take into account water contained inone of the acids or other reagents (in particular, hydrogen peroxide)used in the oxidation reaction.

Before the oxidation reaction is initiated (e.g., by adding orgenerating an oxidizing agent), the oripavine may be present in anypercentage of the reaction mixture. In certain embodiments, it ispresent in a starting amount of from about 1% to about 60%, from about5% to about 50%, from about 10% to about 40%, from about 15% to about35%, from about 20 to about 33%, or from about 20% to about 30% perweight of the complete reaction mixture. In certain preferredembodiments, the oripavine comprises from about 20 to about 33% of thereaction mixture by weight. In certain preferred embodiments, theoripavine comprises from about 20% to about 30% of the reaction mixtureby weight. As the oxidation takes place, the concentration of theoripavine decreases and may finally approach 0%.

The oxidizing agent may be a peracid, a peroxide (which encompasseshydrogen peroxide and peroxide salts), a periodinane, singlet oxygen orany combination thereof. For example, an oxidizing agent may be hydrogenperoxide, potassium peroxymonosulfate (e.g., OXONE®), performic acid,peracetic acid (AcOOH), persulfuric acid, m-chloroperoxybenzoic acid(MCPBA), trifluoro peracetic acid, singlet oxygen, iodosylbenzene, K₂O₂,Na₂O₂, Li₂O₂, Cs₂O₂, Cs₂O₂, K₂SO₅, NaSO₅, or an appropriate mixture ofany two or more of the foregoing. Said oxidizing agent may be eithergenerated in situ in the reaction mixture (e.g., performic acid fromhydrogen peroxide and an acid), or it may be added to the reactionmixture (e.g., MCPBA).

In certain embodiments, the oxidizing agent is a peracid. Said peracidmay either be generated in situ in the reaction mixture from hydrogenperoxide and an acid or from another combination of reagents leading tothe formation of a peracid (e.g., from a peroxide salt and an acid), orit may be added to the reaction mixture (e.g., MCPBA, or a peracidgenerated ex situ, i.e. separately from the reaction mixture before itsaddition to the reaction mixture). If the peracid is generated in situ,the peroxide may be added after the acid and/or at a pH of the reactionmixture which is less than 7.

In certain embodiments, the peracid may be performic acid, peraceticacid, MCPBA, potassium peroxymonosulfate (which contains one peracidgroup), trifluoro peracetic acid, persulfuric acid, or a combination ofany two or more thereof. When said peracid is generated in situ, thecorresponding starting acid is formic acid, acetic acid, 3-chlorobenzoicacid, potassium monosulfate, trifluoroacetic acid, sulfuric acid, or amixture of any two or more of the foregoing.

In certain embodiments, the peracid comprises or is performic acid. Whenthe performic acid is generated in situ or ex situ, it is in oneembodiment generated from formic acid and hydrogen peroxide.

In certain embodiments, the peracid comprises or is a combination ofperformic acid and persulfuric acid. When said combination is generatedin situ or ex situ, it is in one embodiment generated from formic acid,sulfuric acid and hydrogen peroxide.

In certain embodiments, the oxidizing agent is or is generated fromhydrogen peroxide (e.g., added to the reaction mixture in 5, 10, 15, 20,25, 30, 35, 40, 45, 50, 60, or 70% aqueous solution). In certainembodiments, 35% aqueous solution of hydrogen peroxide is added to thereaction mixture. In certain embodiments, at the beginning of thereaction, hydrogen peroxide may comprise about 8-10% of the reactionmixture by volume, and, as the oxidation reaction takes place, theconcentration of hydrogen peroxide decreases and may even reach 0%.

In general, the oxidizing agent, e.g., a peracid generated from an acidand hydrogen peroxide, is present in an amount of from about 0.8 toabout 5 moles per mole of the oripavine. In certain embodiments, fromabout 1 to about 2 moles of the oxidizing agent per 1 mole of theoripavine are utilized. In certain embodiments, about 1, about 1.1,about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.8, orabout 1.9 moles of the oxidizing agent per mole of the oripavine areused. In certain embodiments, from about 1 to about 1.6 moles of theoxidizing agent per mole of the oripavine are utilized. In certainembodiments, from about 1 to about 1.4 moles of the oxidizing agent permole of the oripavine are utilized. In certain embodiments, from about1.2 to about 1.4 moles of the oxidizing agent per mole of the oripavineare utilized. In certain embodiments, from about 1.2 to about 1.3 moles(e.g., 1.25 molar equivalents) of the oxidizing agent per mole of theoripavine are utilized. In certain embodiments, from about 1 to about1.25 moles of the oxidizing agent per mole of the oripavine areutilized. In certain embodiments, from about 1.05 to about 1.15 moles(e.g., 1.05 molar equivalents) of oxidizing agent per mole of theoripavine are used. In embodiments wherein a peracid is generated insitu, the molar amount of the starting component containing the peroxygroup (e.g., hydrogen peroxide) is deemed to represent the molar amountof the resulting peracid in the reaction mixture.

In those embodiments wherein the oxidizing agent is a peracid generatedin situ from hydrogen peroxide and an acid in the reaction mixture,preferably from about 1 to about 1.6 moles of hydrogen peroxide per moleof the oripavine are utilized. In certain embodiments, from about 1 toabout 1.5 moles of hydrogen peroxide per mole of the oripavine areutilized. In certain embodiments, from about 1.2 to about 1.4 moles ofhydrogen peroxide per mole of the oripavine are utilized. In certainembodiments, from about 1.2 to about 1.3 moles (e.g., 1.25 molarequivalents) of the oxidizing agent per mole of the oripavine areutilized. In certain embodiments, from about 1 to about 1.25 moles ofhydrogen peroxide per mole of the oripavine are utilized. In certainembodiments, from about 1.05 to about 1.15 moles (e.g., 1.05 molarequivalents) of hydrogen peroxide per mole of the oripavine are used.

In a preferred embodiment, from about 1 to about 1.5 moles of theoxidizing agent per mole of the oripavine are utilized, and morepreferably, especially in cases where full conversion shall be achievedwithin about 24 hours or less, from about 1.2 to about 1.5 moles or fromabout 1.2 to about 1.4 moles of the oxidizing agent per mole of theoripavine are utilized. This means that in said preferred embodiment,when the oxidizing agent is a peracid generated in situ from hydrogenperoxide and an acid in the reaction mixture, from about 1 to about 1.5moles of hydrogen peroxide per mole of the oripavine are utilized, andmore preferably, from about 1.2 to about 1.4 moles of hydrogen peroxideper mole of the oripavine are utilized. In a particular aspect of saidpreferred embodiment, from about 1.2 to about 1.3 moles (e.g., about1.25 moles) of hydrogen peroxide per mole of the oripavine are utilized.

In those embodiments wherein the oxidizing agent is a peracid generatedin situ from hydrogen peroxide and an acid in the reaction mixture, theacid for generating the peracid preferably is or comprises formic acid.This also encompasses processes wherein the peracid is generated from acombination of formic acid and sulfuric acid.

The molar amount of an acid used for generating a peracid in situ may beless than, equal to, or exceeding the molar amount of the oripavine. Incertain embodiments, an excess of said acid over the amount of theoripavine will be utilized. In certain embodiments, said acid is used inexcess over the amount of the peroxide (e.g., hydrogen peroxide) whichis used to generate the peracid. In certain embodiments, the amount ofthe acid used for generating the peracid (e.g., of formic acid) is fromabout 0.5 to about 14 molar equivalents per molar equivalent of theoripavine, preferably from about 1 to about 12 molar equivalents, morepreferably from about 1 to about 7 molar equivalents, more preferablyfrom about 1.5 to about 6 molar equivalents, more preferably from about2 to about 5 molar equivalents, more preferably from about 2.5 to about4.5 molar equivalents, even more preferably from about 2.5 to 4 molarequivalents per molar equivalent of the oripavine.

In a specific aspect of the oxidation reaction, the molar amount of theacid used for generating the peracid in situ is from about 2.5 to about4.5 equivalents per molar equivalent of the oripavine, and the molaramount of the peroxide is from about 1 to about 1.5 moles, preferablyfrom about 1.2 to about 1.4 moles, more preferably from about 1.2 toabout 1.3 moles per mole of the oripavine. In said aspect, the acid ispreferably formic acid, and the peroxide is preferably hydrogenperoxide.

When an acid is used for generating the oxidizing agent in situ, twoacids may be used during a process encompassing steps (aa) and (bb): afirst acid (which is used to generate at least a part of the peracid insitu in step (aa)), and a second acid (which is the acid H⁺ _(n)X^(n−)of step (bb), which in certain embodiments may also generate a part ofthe peracid in situ in step (aa)). The second acid may be added before,simultaneously with, or after addition of the first acid. In certainembodiments, the acids are pre-mixed and the pre-mixture is added to thesolution or suspension. In certain embodiments, the first acid and thesecond acid may each be independently added all at once or in dividedportions. In certain embodiments, the first acid is formic acid and thesecond acid is sulfuric acid.

The acid H⁺ _(n)X^(n−) of step (bb) may be added as acid H⁺ _(n)X^(n−)or may be generated in situ in the reaction mixture from a saltcontaining an anion X^(n−).

The acid H⁺ _(n)X^(n−) may be added (or generated in situ) before,during or after the oxidation reaction of step (aa), or at anycombination of these time points. It may be added once, in severalbatches or continuously over a certain period of time. It may be addedat or during several points in time in relation to the oxidationreaction, e.g., before, during and after the oxidation, or before andduring the oxidation reaction. If it is added (or generated) beforeand/or during the oxidation reaction, the process comprising steps (aa)and (bb) is performed as a one-pot-reaction. Said one-pot-reaction maybe more cost-, time- and/or volume-efficient and may therefore bepreferred. Especially preferred is a process wherein the acid H⁺_(n)X^(n−) is added to (or generated in) the reaction mixture before theoxidation reaction of step (aa).

In certain embodiments, a portion or all of the acid H⁺ _(n)X^(n−) isadded after some or substantially all of the oripavine has beenoxidized. In certain embodiments, H⁺ _(n)X^(n−) is added aftersubstantially all of the oripavine has been consumed.

In certain embodiments, step (bb) of the process is performed by addingH⁺ _(n)X^(n−) (e.g., H₂SO₄) to the reaction mixture.

H⁺ _(n)X^(n−) may be any acid containing an anion X^(n−) as definedherein. It may, for example, be HCl, H₂SO₄ or its monosalt,methanesulfonic acid, tosylic acid, trifluoroacetic acid, H₃PO₄ or oneof its mono- or disalts, oxalic acid, perchloric acid, or any mixturesthereof. In certain embodiments, it may be HCl, H₂SO₄, methanesulfonicacid, tosylic acid, trifluoroacetic acid, or a mixture thereof. Incertain embodiments, it is H₂SO₄, methanesulfonic acid, ortrifluoroacetic acid or a mixture thereof. In certain embodiments, it istrifluoroacetic acid. In certain embodiments, it is H₂SO₄. In certainembodiments, it is methanesulfonic acid.

H⁺ _(n)X^(n−) may in certain embodiments be polymer supported if n is 2or 3.

The molar amount of H⁺ _(n)X^(n−) present in step (bb) may be the sameas or different from the molar amount of the oripavine provided for step(aa). For example, in embodiments wherein n is 2, the salt or acid addedin step (bb), e.g., H₂SO₄ or a salt thereof, may be added in an amountof from about 0.1 to about 1.5 molar equivalents, preferably of fromabout 0.1 to about 1.2 molar equivalents, more preferably of from about0.1 to about 1 molar equivalents, even more preferably of from about0.25 to about 0.75 molar equivalents, even more preferably of from about0.4 to about 0.6 molar equivalents, even more preferably of from about0.45 to about 0.55 molar equivalents or from about 0.5 to about 0.6molar equivalents per molar equivalent of the oripavine. In certainembodiments wherein n is 2, the salt or acid added in step (bb), e.g.,H₂SO₄ or a salt thereof, is added in an amount of about 0.5 to about 0.6equivalents, e.g. of about 0.51 to about 0.55 molar equivalents permolar equivalent of the oripavine.

In certain embodiments, the amount of H⁺ provided by H⁺ _(n)X^(n−) instep (bb) is in a slight molar excess in comparison to the oripavine. Incertain embodiments, the molar amount of H⁺ _(n)X^(n−) present in step(bb) is within a range of about 1/n+10% to about 1/n+20% molarequivalents per one molar equivalent of the oripavine.

In certain embodiments, the acid H⁺ _(n)X^(n−) is the only acid usedduring the process encompassing steps (aa) and (bb). In thoseembodiments where a peracid is used as oxidizing agent, said acid H⁺_(n)X^(n−) is capable to form a peracid and will be used for generatingsaid peracid.

In certain other embodiments, one or more additional acids are added tothe reaction mixture. In those embodiments where a peracid is used asoxidizing agent, there may be used an acid for generating the peracidwhich is different from the acid H⁺ _(n)X^(n−). This acid is then anadditional acid. In other embodiments, a further additional acid may beadded to the reaction mixture in addition to the acid H⁺ _(n)X^(n−) andthe acid for generating the peracid. Such further acid may be anyremaining acid selected from the acids defined as the acid H⁺ _(n)X^(n−)and as the acid for generating the peracid in the present description,or any mixture of said remaining acids.

The total amount of acid used during steps (aa) and (bb) of theoxidation process is important, because it may influence whether or notthe 14-hydroxymorphinone salt precipitates from the reaction mixtureduring the process. It also determines the amount of base which will berequired after completion of the reaction if a neutralization of thereaction mixture is desired. The total amount of acid includes the acidH⁺ _(n)X^(n−) and, if present, the acid used for generating a peracidand any further acid added to the reaction mixture during steps (aa) and(bb). The total amount of acid may range from about 0.6 to about 14.0molar equivalents of total acid per molar equivalent of the oripavine.

In certain embodiments, from about 1 to about 12 molar equivalents oftotal acid per molar equivalent of the oripavine are used. In certainembodiments, from about 1 to about 10, from about 1 to about 8, fromabout 1 to about 7, from about 1 to about 6.5, from about 1 to about 6,from about 1 to about 5.5, from about 1 to about 5, from about 1 toabout 4.5, from about 1 to about 4, from about 1 to about 3.5, or fromabout 1.5 to about 3.5 molar equivalents of total acid per molarequivalent of the oripavine are used.

In certain embodiments, from about 1 to about 8 molar equivalents,preferably from about 1 to about 5 molar equivalents, more preferablyfrom about 1.5 to about 4.5 molar equivalents, even more preferably fromabout 3 to about 4 molar equivalents of total acid per molar equivalentof the oripavine are used.

In certain embodiments, from about 1.2 to about 4.5 molar equivalents oftotal acid per molar equivalent of the oripavine are used.

In certain embodiments, from about 2.5 to about 5.5 molar equivalents,preferably from about 3 to about 5 molar equivalents of total acid permolar equivalent of the oripavine are used.

In certain embodiments where an acid H⁺ _(n)X^(n−) and an acid used forgenerating the peracid (which is different from H⁺ _(n)X^(n−)) are used,the molar ratio of the acid H⁺ _(n)X^(n−) to the acid used forgenerating the peracid (e.g., of sulfuric acid to formic acid) is fromabout 1:20 to about 1:0.5, from about 1:17 to about 1:1, from about 1:15to about 1:1, from about 1:14 to about 1:1, from about 1:12 to about1:1, from about 1:10 to about 1:1, from about 1:9 to about 1:2, fromabout 1:8 to about 1:3, from about 1:7 to about 1:3, from about 1:7 toabout 1:5, or a numeric value lying within these ranges. In certainembodiments, the molar ratio of the acid H⁺ _(n)X^(n−) to the acid usedfor generating the peracid is from about 1:9 to about 1:4, preferablyfrom about 1:7.5 to about 1:4, more preferably from about 1:7 to about1:5, or a numeric value lying within these ranges.

In certain embodiments, from about 2.5 to about 4.5 molar equivalents ofthe acid used for generating a peracid per molar equivalent of theoripavine are used, and from about 0.1 to about 1.5, from about 0.1 toabout 1, from about 0.2 to about 0.9, from about 0.25 to about 0.75,from about 0.4 to about 0.6, or from about 0.5 to about 0.6 molarequivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of theoripavine are used. In said embodiments, said first acid may be formicacid, and said second acid may be sulfuric acid.

In certain embodiments, from about 0.5 to about 4 molar equivalents ofthe acid used for generating a peracid per molar equivalent of theoripavine are used, and from about 0.1 to about 1.5, from about 0.1 toabout 1, from about 0.2 to about 0.9, from about 0.25 to about 0.75,from about 0.4 to about 0.6, or from about 0.5 to about 0.6 molarequivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of theoripavine are used. In said embodiments, said first acid may be formicacid, and said second acid may be sulfuric acid.

In certain embodiments, from about 0.5 to about 3.5 molar equivalents ofthe acid used for generating a peracid per molar equivalent of theoripavine are used, and from about 0.1 to about 1.5, from about 0.1 toabout 1, from about 0.2 to about 0.9, from about 0.25 to about 0.75,from about 0.4 to about 0.6, or from about 0.5 to about 0.6 molarequivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of theoripavine are used. In said embodiments, said first acid may be formicacid, and said second acid may be sulfuric acid.

In certain embodiments, from about 1 to about 3 molar equivalents of theacid used for generating a peracid per molar equivalent of the oripavineare used, and from about 0.4 to about 0.6, or from about 0.5 to about0.6 molar equivalents of the acid H⁺ _(n)X^(n−) per molar equivalent ofthe oripavine are used. In said embodiments, said first acid may beformic acid, and said second acid may be sulfuric acid.

In a preferred embodiment utilizing formic acid and sulfuric acid, theoxidation is performed by oxidizing the oripavine in the presence ofabout 12 molar equivalents or less, about 10 molar equivalents or less,about 8 molar equivalents or less, about 7 molar equivalents or less,about 6 molar equivalents or less, about 5 molar equivalents or less,about 4 molar equivalents or less, about 3 molar equivalents or less,about 2 molar equivalents or less, or about 1 molar equivalents (e.g.,1.05 molar equivalents) or less of total acid per one molar equivalentof the oripavine, wherein from about 0.1 to about 1.5 molar equivalentsof total acid comes from the acid H⁺ _(n)X^(n−). In one particularembodiment, the oripavine is oxidized to the 14-hydroxymorphinone saltby exposing each molar equivalent of the oripavine to (i) from about 1.0to about 1.6, preferably from about 1.2 to about 1.4 molar equivalentsof hydrogen peroxide, (ii) from about 0.3 to about 9, from about 0.5 toabout 8, from about 0.5 to about 4.5, or from about 2.5 to about 4.5molar equivalents of the acid used for generating the peracid, and (iii)from about 0.1 to about 1.5, from about 0.25 to about 0.9, or from about0.4 to about 0.6 molar equivalents of the acid H⁺ _(n)X^(n−). In certainembodiments, from about 2.5 to about 4 molar equivalents of the acidused for generating the peracid per one molar equivalent of theoripavine are used. In certain embodiments, from about 0.4 to about 0.6molar equivalents of the acid H⁺ _(n)X^(n−), and from about 2.5 to about4 molar equivalents of the acid used for generating the peracid areused. In certain embodiments, from about 0.4 to about 0.6 molarequivalents of the acid H⁺ _(n)X^(n−), and from about 1 to about 3 molarequivalents of the acid used for generating the peracid are used. Incertain embodiments, from about 0. 5 to about 0.6 molar equivalents ofthe acid H⁺ _(n)X^(n−), and from about 2.5 to about 4.5 molarequivalents of the acid used for generating the peracid are used. Incertain embodiments, conducting the oxidation reaction under theseconditions may improve the volume efficiency of the reaction and mayreduce the number and amounts of by-products formed during the oxidationreaction.

In certain embodiments, a portion or all of the H⁺ _(n)X^(n−) (e.g.,H₂SO₄) is added to the reaction mixture before the acid or the peroxideused for generating the peracid is added, or at the same point in time.

In certain embodiments, H⁺ _(n)X^(n−) (e.g., H₂SO₄) is added after theacid used for generating the peracid (e.g., formic acid). In certainembodiments, the reaction mixture may already comprise formic acid, andsulfuric acid is then added.

In preferred embodiments, the 14-hydroxymorphinone salt is precipitatedfrom the reaction mixture, either because the presence of the acid H⁺_(n)X^(n−) (e.g., H₂SO₄) induces the precipitation of the14-hydroxymorphinone salt or a solvate thereof during the oxidationreaction, or because in addition to said presence the precipitation isstarted or enhanced by other measures, e.g., by adjusting thetemperature of the solution and/or adding a suitable antisolvent to thesolution, as described in more detail below. In certain embodiments,precipitation is achieved by adding a suitable antisolvent. In certainembodiments, precipitation is achieved by lowering the temperature belowthe reaction temperature of the oxidation reaction.

The reaction steps (aa) and (bb) are typically performed in a solvent.The amount of said solvent is described above with regard to molarity.

In certain embodiments, the oxidizing agent is or comprises performicacid generated, e.g., from hydrogen peroxide and formic acid, and thesolvent is water, an alcohol, a mixture of two or more alcohols, or amixture of an alcohol and water. The solvent may be methanol or amixture of methanol and water. The solvent may be isopropanol or amixture of isopropanol and water. The solvent may be water.

In certain embodiments, the oxidizing agent is or comprises performicacid and persulfuric acid generated, e.g., from hydrogen peroxide andformic acid and sulfuric acid, and the solvent is water, an alcohol, amixture of two or more alcohols, or a mixture of an alcohol and water.The solvent may be methanol or a mixture of methanol and water. Thesolvent may be isopropanol or a mixture of isopropanol and water. Thesolvent may be water.

In certain embodiments, the oxidizing agent is or comprises peraceticacid, and the solvent is water, an alcohol, a mixture of two or morealcohols, or a mixture of an alcohol and water.

In certain embodiments, step (aa) is performed with an oxidizing agentformed from an acid and hydrogen peroxide. In certain embodiments, theamount of total acid present in the reaction mixture is about 12 molarequivalents or less, about 10 molar equivalents or less, about 8 molarequivalents or less, about 7 molar equivalents or less, about 6 molarequivalents or less, about 5 molar equivalents or less, about 4 molarequivalents or less, about 3 molar equivalents or less, about 2 molarequivalents or less, or about 1 molar equivalents (e.g., 1.05 molarequivalents) or less per molar equivalent of oripavine. In oneparticular embodiment, the oripavine is oxidized to the14-hydroxymorphinone by exposing each molar equivalent of the oripavineto from about 1.0 to about 1.6, preferably from about 1.2 to about 1.4molar equivalents of hydrogen peroxide, from about 0.3 to about 9 molarequivalents, from about 0.5 to about 8 molar equivalents, or from about2.5 to about 4.5 molar equivalents of formic acid, and from about 0.4 toabout 0.6 molar equivalents of sulfuric acid. In certain embodiments,from about 0.5 to about 5 molar equivalents of formic acid per one molarequivalent of oripavine are used. In certain embodiments, from about 2.5to about 4.5 molar equivalents of formic acid per one molar equivalentof oripavine are used. In certain embodiments, from about 2.5 to about 4molar equivalents of formic acid per one molar equivalent of oripavineare used.

In certain embodiments, the oxidation process is performed by: (i)forming a solution or a suspension comprising oripavine and from about1.5 to about 4 molar equivalents of a first acid (e.g., formic acid) permolar equivalent of oripavine, (ii) adding from about 0.4 to about 0.6molar equivalents of the acid H⁺ _(n)X^(n−) (e.g., sulfuric acid) permolar equivalent of oripavine to the solution or the suspension, (iii)adding from about 1 to about 1.6 molar equivalents of hydrogen peroxideto the solution or the suspension from (ii), and (iv) precipitating the14-hydroxymorphinone salt from the solution or suspension (e.g., byadjusting the temperature of the solution and/or adding a suitableantisolvent to the solution, as described in more detail below). Incertain embodiments, precipitation is achieved by adding a suitableantisolvent. In certain embodiments, precipitation is achieved bylowering the temperature below the reaction temperature of the oxidationreaction.

In certain embodiments, the oxidation process is performed by: (i)forming a solution or a suspension comprising oripavine and from about2.5 to about 4.5 molar equivalents of a first acid (e.g., formic acid)per molar equivalent of oripavine, (ii) adding from about 0.5 to about0.6 molar equivalents of the acid H⁺ _(n)X^(n−) (e.g., sulfuric acid)per molar equivalent of oripavine to the solution or the suspension,(iii) adding from about 1.0 to about 1.4 molar equivalents, preferablyfrom about 1.2 to about 1.4 molar equivalents, and more preferably fromabout 1.2 to about 1.3 molar equivalents of hydrogen peroxide to thesolution or the suspension from (ii), and (iv) precipitating the14-hydroxymorphinone salt from the solution or suspension (e.g., byadjusting the temperature of the solution and/or adding a suitableantisolvent to the solution, as described in more detail below). Incertain embodiments, precipitation is achieved by adding a suitableantisolvent. In certain embodiments, precipitation is achieved bylowering the temperature below the reaction temperature of the oxidationreaction.

In certain embodiments, the amount of 8-hydroxyoxymorphone in theoxidation reaction product containing the 14-hydroxymorphinone salt isless than about 2500 ppm, less than about 2000 ppm, less than about 1500ppm, less than about 1000 ppm, less than about 500 ppm, less than about100 ppm, less than about 50 ppm, less than about 10 ppm, less than about5 ppm, or less than about 1 ppm of the 14-hydroxymorphinone. In certainembodiments, the amount of 8-hydroxyoxymorphone in the reaction productcontaining the 14-hydroxymorphinone salt is the amount described inSection V. In certain embodiments, the oxidation reaction product isfree from 8-hydroxyoxymorphone.

In certain embodiments, oripavine is oxidized to 14-hydroxymorphinone,wherein the reaction mixture comprises more than one acid (e.g., twoacids), and comprises less than about 14 molar equivalents of total acidper molar equivalent of oripavine (e.g., from about 0.5 to about 11,from about 1 to about 10.5, from about 1.5 to about 5, or from about 3to about 5 molar equivalents of acid per molar equivalent of oripavine).

In certain embodiments, oripavine is oxidized to 14-hydroxymorphinone,wherein the reaction mixture comprises more than one acid (e.g., twoacids), and comprises less than about 8 molar equivalents of total acidper molar equivalent of oripavine (e.g., from about 0.5 to about 7, fromabout 1 to about 5, from about 1.2 to about 4.5, from about 2.5 to about4.5, or from about 3 to about 4 molar equivalents of total acid permolar equivalent of oripavine).

In certain embodiments of the process, oripavine is oxidized to14-hydroxymorphinone in a solution or suspension containing a mixture offormic acid and sulfuric acid, the mixture comprising not more thanabout 14 molar equivalents of total acid per one molar equivalent oforipavine (e.g., from about 0.5 to about 11, from about 1 to about 10.5,from about 1.5 to about 5, or from about 3 to about 5 molar equivalentsof acid per one molar equivalent of oripavine).

There are also alternative ways to perform step (bb) than by adding H⁺_(n)X^(n−) to the reaction mixture. In step (bb) of the process, the H⁺_(n)X^(n−) can be generated by adding a salt containing X^(n−). Saidsalt may have the formulaM^(m+)(H⁺)_((n−m))X^(n−), or M^(m+) _(((n−l)/m))(H⁺)_(l)X^(n−), wherein

-   M^(m+) is a monovalent or polyvalent metal cation;-   m and n are independently from each other an integer selected from    1, 2, and 3, provided that m is ≤n; and-   l is an integer selected from 0, 1, and 2, provided that l<n.

The metal cation may be an alkali metal cation, an alkaline earth metalcation or a Group III cation. Exemplary cations are Na⁺, K⁺, Ca²⁺.Exemplary salts are NaHSO₄, KHSO₄, Na₂SO₄, K₂SO₄, NaH₂PO₄, Na₂HPO₄,Na₃PO₄, KH₂PO₄, K₂HPO₄, K₃PO₄.

The oxidation reaction may be prepared in any suitable reaction vessel.In certain embodiments, the reaction vessel is a flow reactor. Incertain other embodiments, the reaction vessel is not a flow reactor. Incertain embodiments, the reaction vessel is a continuous flow reactor.In certain other embodiments, the reaction vessel is not a continuousflow reactor.

Precipitation and/or Isolation of the 14-Hydroxymorphinone Salt

The 14-hydroxymorphinone salt or the solvate thereof may be provided asa solid, or in solution or suspension as a result of the oxidationprocess encompassing steps (aa) and (bb). In certain preferredembodiments, the process is performed under conditions wherein the14-hydroxymorphinone salt or a solvate thereof is insoluble in thereaction mixture. In these embodiments, the process may comprise anadditional step (cc) of precipitating the 14-hydroxymorphinone salt orthe solvate thereof from the reaction mixture.

As already pointed out in the Definitions section, “precipitating”encompasses “crystallizing” unless stated otherwise.

The precipitation may start as soon as H⁺ _(n)X^(n−) is present in thereaction mixture (e.g., after addition of an acid H⁺ _(n)X^(n−)), or itmay start at a later point in time. In other words, it may take placeduring and/or after the oxidation reaction.

The precipitation of the 14-hydroxymorphinone salt or the solvatethereof may be caused by the presence of the acid H⁺ _(n)X^(n−) in thereaction mixture. It may be enhanced by adding an additional amount ofthe acid H⁺ _(n)X^(n−) or the salt containing X^(n−) to the reactionmixture during step (bb).

In certain embodiments, the precipitation of the 14-hydroxymorphinonesalt or the solvate thereof may require the cooling of the reactionmixture and/or the addition of an antisolvent.

In certain embodiments wherein the 14-hydroxymorphinone salt or asolvate thereof precipitates from the reaction mixture, the acid H⁺_(n)X^(n−) is H₂SO₄ or its monosalt, methanesulfonic acid, tosylic acid,trifluoroacetic acid, H₃PO₄ or one of its mono- or disalts, oxalic acid,perchloric acid, or any mixtures thereof. In certain embodiments, it maybe H₂SO₄, methanesulfonic acid, tosylic acid, trifluoroacetic acid, or amixture thereof. In certain embodiments, it is H₂SO₄, methanesulfonicacid, or trifluoroacetic acid or a mixture thereof. In certainembodiments, it is trifluoroacetic acid. In certain embodiments, it isH₂SO₄. In certain embodiments, it is methanesulfonic acid. Preferably,it is H₂SO₄.

The 14-hydroxymorphinone salt or the solvate thereof, once precipitated,may either be isolated (i.e. separated from the reaction mixture), or itmay be converted without preceding isolation to oxymorphone or a salt orsolvate thereof. Preferably, it is isolated before the hydrogenationprocess of the present invention is performed.

Precipitation of the 14-hydroxymorphinone salt may be influenced by themolar ratio of the anion X^(n−) to the oripavine (see above), by theamount of total acid present during the oxidation reaction (as comparedto molar equivalents of the oripavine), by the temperature before,during or after the oxidation reaction, by the kind and amount ofsolvent (e.g., water) present in the reaction mixture, by the presenceof an antisolvent added to the reaction mixture, by the rate at whichthe reactants are added during the process to the reaction mixture, orby a combination of any of the foregoing.

In certain embodiments, the precipitation of the 14-hydroxymorphinonesalt or a solvate thereof is initiated and/or enhanced by one or more ofthe following:

-   (i) adjusting (e.g., lowering) the temperature of the reaction    mixture to the precipitation temperature;-   (ii) addition of an antisolvent;-   (iii) addition of a seed crystal;-   (iv) lowering the pH;-   (v) changing the ionic strength of the reaction mixture (e.g., by    addition of a salt);-   (vi) concentrating the reaction mixture;-   (vii) reducing or stopping agitation of the reaction mixture;    or any other conventional method for initiating or enhancing    precipitation or crystallization.

When the temperature is adjusted to the precipitation temperature, thismeans that the precipitation of the 14-hydroxymorphinone salt or thesolvate thereof is initiated and/or enhanced by adjusting thetemperature of the reaction mixture to or beyond a temperature at whichsaid compound precipitates (“precipitation temperature”). Thetemperature is either adjusted by performing the oxidation reaction atthe precipitation temperature, or by lowering the temperature of thereaction mixture during the reaction or after completion of thereaction.

In certain embodiments, the reaction mixture is adjusted to atemperature of ≤40° C. to initiate precipitation, i.e. the precipitationtemperature is ≤40° C. In certain embodiments, the precipitation isinitiated at a precipitation temperature of about −20° C., about −15°C., about −10° C., about −5° C., about 0° C., about 5° C., about 10° C.,about 15° C., about 17° C., about 19° C., about 21° C., about 23° C.,about 25° C., about 27° C., about 29° C., about 31° C., about 33° C.,about 35° C., about 37° C., or about 40° C.

In certain embodiments, the precipitation temperature is in a range offrom about −20° C. to about 40° C., preferably from about 0° C. to about40° C., more preferably from about 5° C. to about 35° C., morepreferably from about 5° C. to about 30° C., even more preferably fromabout 5° C. to about 20° C.

In certain embodiments, the precipitation temperature is in a range offrom about 5° C. to about 22° C., preferably from 5° C. to about 18° C.,more preferably from about 8° C. to about 15° C.

In certain embodiments, the precipitation temperature is in a range offrom about 5° C. to about 18° C.; or from about 8° C. to about 15° C.

In certain embodiments, an antisolvent is used in addition to adjustingthe temperature to the precipitation temperature. In certainembodiments, e.g., when the 14-hydroxymorphinone salt is14-hydroxymorphinone sulfate, precipitation will also occur withoutadding an antisolvent.

If an antisolvent is used for initiating precipitation, theprecipitation temperature may be in a range of from about −20° C. toabout 40° C., from about 0° C. to about 40° C., from about 5° C. toabout 35° C., from about 5° C. to about 22° C., from about 5° C. toabout 18° C.; or from about 8° C. to about 15° C.

In certain embodiments, the reaction mixture is cooled at a controlledrate during precipitation. In certain embodiments, the cooling rate isabout 1° C., about 2° C., about 3° C., about 4° C., or about 5° C. perhour.

An important factor influencing the precipitation of a14-hydroxymorphinone salt or a solvate thereof in the oxidation processmay be the temperature of the reaction mixture. A further factorinfluencing the precipitation appears to be the total amount of acid inthe reaction mixture. Another factor influencing the precipitationappears to be the molarity of the reaction mixture. The addition of anantisolvent also appears to be a factor that can influence precipitationof a 14-hydroxymorphinone salt or a solvate thereof. It is presentlybelieved that the precipitation temperature will rise when the totalamount of acid is lowered.

Hence, in a process wherein the 14-hydroxymorphinone salt or the solvatethereof is precipitated and wherein the total amount of acid present inthe reaction mixture is from about 0.6 to about 14.0 molar equivalentsof total acid per molar equivalent of oripavine, the precipitationtemperature may be ≤40° C. (i.e. 40° C. or less). In a process whereinthe total amount of acid present in the reaction mixture is from about 1to about 8 molar equivalents, preferably from about 1 to about 5 molarequivalents of total acid per molar equivalent of the oripavine, theprecipitation temperature may be in a range of from about 0° C. to about40° C., preferably from about 0° C. to about 35° C. In a process whereinthe total amount of acid present in the reaction mixture is from about 1to about 4 molar equivalents, preferably from about 1 to about 3 molarequivalents of total acid per molar equivalent of the oripavine, theprecipitation temperature may be in a range of from about 5° C. to about22° C.; preferably from about 8° C. to about 20° C., more preferablyfrom about 8° C. to about 15° C. Further examples of such correlationscan be found in the Examples section of PCT/IB2013/001541.

In certain embodiments, an antisolvent is added to precipitate a14-hydroxymorphinone salt or a solvate thereof. When an antisolvent isadded to the reaction mixture, it is added either during or after step(bb) and in an effective amount to initiate and/or enhanceprecipitation. In certain embodiments, addition of a suitableantisolvent increases the yield of the reaction. Addition of a suitableantisolvent may also enhance retention of 8-hydroxyoxymorphone in thesupernatant. A suitable antisolvent may comprise or consist oftert-butyl methyl ether, diethyl ether, hexane(s), tert-amyl alcohol,methanol, ethanol, isopropanol, 2-butanol, heptanes, xylenes, toluene,acetone, 2-butanone, ethyl acetate, tetrahydrofuran, 1,2-dichloroethane,chloroform, dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol,n-propanol, 1-butanol, tert-butanol, isobutanol, isopropyl acetate,1,4-dioxane, 2-methyl-tetrahydrofuran, methyl formate, methyl acetate,or a mixture of two or more of any of the foregoing.14-Hydroxymorphinone sulfate has very low/no solubility in thesesolvents at room temperature. The listed alcohols and ethers are thepreferred antisolvents. In some embodiments, said antisolvent is analcohol, e.g., methanol, isopropanol or 2-butanol. In some embodiments,said antisolvent is an ether, e.g., tert-butyl methyl ether and/ortetrahydrofuran. In some preferred embodiments, said antisolvent isisopropanol or 2-butanol. In some embodiments, said antisolvent is amixture of an alcohol (e.g., methanol) and an ether (e.g., tert-butylmethyl ether and/or tetrahydrofuran), for example a mixture of methanoland tert-butyl methyl ether, or a mixture of methanol andtetrahydrofuran, or a mixture of tert-butyl methyl ether andtetrahydrofuran, or a mixture of methanol, tert-butyl methyl ether, andtetrahydrofuran. When two or more antisolvents are used (e.g., in amixture), they can be added as a mixture or separately.

When an antisolvent is added, it is preferably added in an amount offrom about 0.5 to about 7 mL antisolvent per 1 g oripavine, morepreferably in an amount of from about 0.5 to about 5 mL antisolvent per1 g oripavine, more preferably in an amount of from about 0.5 to about 4mL antisolvent per 1 g oripavine. For example, in a preferredembodiment, from about 1 to about 4 mL 2-butanol (e.g., 3.6 mL) per 1 gof oripavine are added. Within these ranges, the yield is especiallyincreased and/or the retention of 8-hydroxyoxymorphone in thesupernatant is especially enhanced.

When a seed crystal is added, said seed crystal is a crystal of the14-hydroxymorphinone salt or a solvate thereof. This seed crystal mayact as crystallization nucleus if the solution of the14-hydroxymorphinone salt resulting from step (bb) is metastable. It maybe made metastable by concentrating the reaction mixture.

In certain embodiments, the precipitate may be isolated from thereaction mixture (isolation step (dd)).

In said isolation step (dd), the precipitate may be separated from thesupernatant in any conventional manner, e.g., by filtration,centrifugation, decanting, or any other conventional method forseparating a solid phase from a liquid phase. In certain embodiments,the ratio of 8-hydroxyoxymorphone (either in its free base form or boundin a salt or solvate) to 14-hydroxymorphinone (which may be bound in the14-hydroxymorphinone salt) in the precipitate is less than the ratio of8-hydroxyoxymorphone to 14-hydroxymorphinone in the supernatant.

In cases where the 14-hydroxymorphinone salt or a solvate thereof is notprecipitated, it may be isolated by concentrating the reaction mixture,e.g., by drying, vacuum distillation, spray drying or lyophilization.

Further Processing of the 14-Hydroxymorphinone Salt or the SolvateThereof

In certain embodiments, the precipitate containing the14-hydroxymorphinone salt or the solvate thereof can be furtherprocessed.

In certain embodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof may be washed with and/or(re)crystallized in an organic solvent or aqueous solvent in which8-hydroxyoxymorphone or a salt or solvate thereof is more soluble thanthe 14-hydroxymorphinone salt or solvate thereof. The washing and/or(re)crystallization may further reduce the amount of8-hydroxyoxymorphone in the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof. The washing and/or the(re)crystallization may be performed more than once, or they may also becombined sequentially.

In certain embodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or is(re)crystallized in a solvent containing or consisting of an ether, aketone, an ester, an alcohol, water, an (optionally halogenated) alkane,an (optionally halogenated) aromatic solvent or any mixtures thereof.The solvent may contain or consist of one or more of the followingsolvents: methanol, ethanol, isopropanol, 1-butanol, 2-butanol,isobutanol, tert-butanol, acetone, tetrahydrofuran, ethyl acetate,heptane, tert-butyl methyl ether, 1,2-dichloroethane, toluene,2-butanone (MEK), tert-amyl alcohol, chloroform, xylene, and water.

In certain embodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed and/or(re)crystallized in a solvent consisting of an ether, an alcohol, water,chloroform, or any mixture thereof. In certain embodiments, said solventmay be methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol,isobutanol, tert-butanol, acetone, tetrahydrofuran, chloroform, or amixture of water with any of the foregoing.

In certain embodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed and/or(re)crystallized with a solvent which is tert-butyl methyl ether,tetrahydrofuran, methanol, ethanol, acetone, isopropanol, 2-butanol, ora mixture of methanol:water, THF:water, acetone:water,isopropanol:water, 2-butanol:water, or ethanol:water. In certainembodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed and/or(re)crystallized with a solvent which is tert-butyl methyl ether,tetrahydrofuran, methanol, a 2-butanol:water mixture, or amethanol:water mixture.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 90:10 methanol:water mixture; 80:20 methanol:watermixture, 70:30 methanol:water or 60:40 methanol:water mixture. Incertain embodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 80:20 or 70:30 methanol:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 90:10 ethanol:water mixture, 80:20 ethanol:watermixture or 70:30 ethanol:water mixture. In certain embodiments, theisolated precipitate containing the 14-hydroxymorphinone salt or solvatethereof is washed with and/or (re)crystallized in 90:10 ethanol/watermixture. 8-Hydroxyoxymorphone (and its corresponding protonated species)is more soluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in tetrahydrofuran or in 90:10 tetrahydrofuran:watermixture. 8-Hydroxyoxymorphone (and its corresponding protonated species)is more soluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 90:10 isopropanol:water mixture, 80:20isopropanol:water mixture or 70:30 isopropanol:water mixture. In certainembodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 90:10 isopropanol:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 90:10 2-butanol:water mixture, 80:202-butanol:water mixture, 70:30 2-butanol:water mixture, 60:402-butanol:water mixture, or 20:10 2-butanol:water mixture. In certainembodiments, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 20:10 2-butanol:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

In certain embodiments, preferably wherein the 14-hydroxymorphinone saltis 14-hydroxymorphinone sulfate, the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof is washed with and/or(re)crystallized in a 70:30 acetone:water mixture or 80:20 acetone:watermixture. 8-Hydroxyoxymorphone (and its corresponding protonated species)is more soluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that 8-hydroxyoxymorphone may be removed fromthe isolated 14-hydroxymorphinone salt or solvate thereof by the washingand/or (re)crystallization.

The washing of the isolated precipitate containing the14-hydroxymorphinone salt or solvate thereof may be performed in any wayconventional in the art, e.g., by forming a slurry of the compound.

In certain embodiments, the ratio of 8-hydroxyoxymorphone to14-hydroxymorphinone in the supernatant after the precipitation of the14-hydroxymorphinone salt or solvate thereof is higher than the ratio of8-hydroxyoxymorphone to 14-hydroxymorphinone in the precipitate.

Preferred Process Conditions

A preferred set of reaction conditions for the oxidation process and thesubsequent isolation of the 14-hydroxymorphinone salt is described inthe following. Therein, the 14-hydroxymorphinone salt is preferably14-hydroxymorphinone sulfate.

The process is performed by: (i) forming a solution or a suspensioncomprising the oripavine, from about 1.5 to about 2.0 mL water per goripavine, and from about 2.5 to about 4.5 molar equivalents of formicacid per molar equivalent of oripavine, (ii) adding from about 0.5 toabout 0.6 molar equivalents of sulfuric acid per molar equivalent of theoripavine to the solution or the suspension, (iii) adding from about 1.0to about 1.4 molar equivalents, preferably from about 1.2 to about 1.4molar equivalents, more preferably from about 1.2 to about 1.3 molarequivalents of hydrogen peroxide to the solution or the suspension from(ii), then incubating the mixture at a temperature of from about 30° C.to about 38° C., preferably of from about 32° C. to about 36° C., morepreferably of about 35° C., until the conversion is complete, and (iv)precipitating the 14-hydroxymorphinone salt from the resulting solutionor suspension. Step (iv) may be performed by adding a suitableantisolvent to the solution, as described in detail above. A preferredantisolvent may be an alcohol, in particular isopropanol or 2-butanol.Preferably, from about 2 to about 4 mL antisolvent per 1 g oripavine areadded.

When the 14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, theprocess is preferably performed by: (i) forming a solution or asuspension by mixing the oripavine, from about 1.5 to about 2.0 mL waterper g oripavine, and from about 2.5 to about 4.5 molar equivalents offormic acid per molar equivalent of oripavine, (ii) adding from about0.5 to about 0.6 molar equivalents of sulfuric acid per molar equivalentof oripavine to the solution or the suspension, (iii) adding from about1.0 to about 1.4 molar equivalents, preferably from about 1.2 to about1.4 molar equivalents, more preferably from about 1.2 to about 1.3 molarequivalents of hydrogen peroxide to the solution or the suspension from(ii), then incubating the mixture at a temperature of from about 30° C.to about 38° C., preferably of from about 32° C. to about 36° C., morepreferably of about 35° C., until the conversion is complete, and (iv)precipitating the 14-hydroxymorphinone sulfate from the resultingsolution or suspension. Step (iv) may be performed by adding a suitableantisolvent to the solution, as described in detail above. A preferredantisolvent may be an alcohol, in particular isopropanol or 2-butanol.Preferably, from about 2 to about 4 mL antisolvent per 1 g oripavine areadded.

In the oxidation process, the formation of the 14-hydroxymorphinone saltor a solvate thereof may have the effect that less 8-hydroxy compound isformed during the oxidation reaction in comparison to an oxidationreaction where no 14-hydroxymorphinone salt or solvate thereof isformed. In other words, the formation of the 14-hydroxymorphinone saltallows for an improvement of the by-product profile of the reactionproduct. One example for such oxidation reaction may be the formation ofa 14-hydroxymorphinone salt wherein n is 2 and preferably wherein X^(n−)is sulfate. Another example for such oxidation reaction may be theformation of a 14-hydroxymorphinone salt wherein n is 1 and preferablywherein X^(n−) is trifluoroacetate.

The formation of the 14-hydroxymorphinone salt or a solvate thereof mayalso have the effect that 8-hydroxyoxymorphone can be separated from the14-hydroxymorphinone salt or the solvate thereof, e.g., by precipitationof the 14-hydroxymorphinone salt or the solvate thereof from thereaction mixture. One example for such an effect may be the formation ofa 14-hydroxymorphinone salt wherein X^(n−) is sulfate. One example forsuch an effect may be the use of one of the antisolvents described inthe present Section IV.

A combination of these effects may also take place. That is, both less8-hydroxyoxymorphone is formed during the oxidation and said compoundcan be separated from the 14-hydroxymorphinone salt or solvate thereof.One example may be the formation of a 14-hydroxymorphinone salt whereinX^(n−) is sulfate, preferably in combination with one of theantisolvents described in the present Section IV.

V. 14-Hydroxymorphinone Salt

The present invention uses a 14-hydroxymorphinone salt having thefollowing formula or a solvate thereof

wherein X^(n−) and n are defined as above, in particular in Section I,as starting material for the hydrogenation process according to theinvention. Present invention may use said 14-hydroxymorphinone salt orsolvate thereof as a solid, in solution or as a suspension.

The 14-hydroxymorphinone salt or solvate thereof comprises one or moreprotonated molecules of 14-hydroxymorphinone and at least one anionX^(n−). The anion may be an organic or inorganic anion. The anion may bemono- or polyvalent (e.g., divalent or trivalent). In its solid form,the components of the 14-hydroxymorphinone salt are present instoichiometric amounts. However, other molecular ratios may also bepresent either in micro- or macrostructures of the salt, depending e.g.,on the type of the anion and valency thereof, the solvent (which mightalso form part of the salt) and the ambient pH.

In certain embodiments, said 14-hydroxymorphinone salt or solvatethereof is provided in its isolated, solid form, which in certainembodiments is its crystalline form, as starting material for thehydrogenation reaction.

Said 14-hydroxymorphinone salt or solvate thereof may be obtainable orobtained by the process described in Section IV. Preferably, it isobtained by said process.

Said 14-hydroxymorphinone salt or solvate thereof is a starting materialor intermediate for the hydrogenation reaction according to the presentinvention which results in the synthesis of oxymorphone or(pharmaceutically acceptable) salts or solvates thereof.

In certain embodiments of the 14-hydroxymorphinone salt or solvatethereof, n is 1 or 2, and is preferably 2.

In certain embodiments, X^(n−) is SO₄ ²⁻ or trifluoroacetate, and ispreferably SO₄ ²⁻.

In certain embodiments, the 14-hydroxymorphinone salt is provided as itssolvate. Said solvate may be any association product of a14-hydroxymorphinone salt with a solvent molecule. The molar ratio ofsolvent molecule(s) per molecule of 14-hydroxymorphinone salt may vary.The molar ratio of solvent to compound/salt in the solvate may be 1(e.g., in a monohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in apolyhydrate), or less than 1 (e.g., in a hemihydrate). The molar rationeed not be an integer ratio, it can also be, e.g., 0.5 (as in ahemihydrate) or 2.5. For example, 1 molecule water per molecule of14-hydroxymorphinone sulfate is bound in 14-hydroxymorphinone sulfatemonohydrate. The solvate of the 14-hydroxymorphinone salt is in certainembodiments a hydrate, for example a monohydrate, dihydrate, trihydrate,tetrahydrate, pentahydrate or hexahydrate, or a hydrate wherein theratio of water per molecule is not necessarily an integer, but withinthe range of from 0.5 to 10.0. In certain embodiments, the solvate ofthe 14-hydroxymorphinone salt is a hydrate wherein the ratio of waterper molecule is within the range of from 1 to 8. In certain embodiments,the solvate of the 14-hydroxymorphinone salt is a hydrate wherein theratio of water per molecule is within the range of from 1 to 6, i.e. amono- to hexahydrate. In certain embodiments, the solvate of the14-hydroxymorphinone salt is a monohydrate or a pentahydrate.

In certain embodiments, the 14-hydroxymorphinone salt is

or a solvate thereof. The solvate may be a hydrate. The molar ratio ofsolvent to compound/salt in the solvate may be 1 (e.g., in amonohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), orless than 1 (e.g., in a hemihydrate). The molar ratio need not be aninteger ratio, it can also be, e.g., 0.5 (as in a hemihydrate) or 2.5.For example, 1 molecule water per molecule of 14-hydroxymorphinonesulfate is bound in 14-hydroxymorphinone sulfate monohydrate. Thesolvate is in certain embodiments a hydrate, for example a monohydrate,dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate, or ahydrate wherein the ratio of water per molecule is not necessarily aninteger, but within the range of from 0.5 to 10.0. In certainembodiments, the solvate is a hydrate wherein the ratio of water permolecule is within the range of from 1 to 8. In certain embodiments, thesolvate is a hydrate wherein the ratio of water per molecule is withinthe range of from 1 to 6, i.e. a mono- to hexahydrate. In certainembodiments, the solvate is a monohydrate or a pentahydrate.

Pharmaceutical compositions and dosage forms produced from said14-hydroxymorphinone salt or solvate thereof, preferably, contain less8-hydroxyoxymorphone and/or 14-hydroxymorphinone than pharmaceuticalcompositions prepared via a different intermediate, i.e. without the14-hydroxymorphinone salt.

In certain embodiments, the 14-hydroxymorphinone salt is prepared asdescribed in Section IV.

In certain embodiments, the 14-hydroxymorphinone salt or solvate thereofadditionally comprises 8-hydroxyoxymorphone.

Said 8-hydroxyoxymorphone is a by-product of the oxidation reactiondescribed above, as illustrated in the following reaction Scheme 17:

Said 8-hydroxyoxymorphone may be present in the form of its free base,or in the form of its salt or solvate.

Whenever 8-hydroxyoxymorphone is comprised in the 14-hydroxymorphinonesalt (thus forming a composition), it is present in a certain amountwhich shall be specified in the following.

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 2500 ppm, less than about 2250 ppm, less than about2000 ppm, less than about 1750 ppm, less than about 1500 ppm, or lessthan about 1250 ppm of the 14-hydroxymorphinone salt (HPLC peak arearatio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 1000 ppm, less than about 750 ppm, less than about500 ppm, or less than about 400 ppm of the 14-hydroxymorphinone salt orsolvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 300 ppm, less than about 275 ppm, less than about 250ppm, less than about 225 ppm, less than about 200 ppm, less than about175 ppm, less than about 150 ppm, or less than about 125 ppm of the14-hydroxymorphinone salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 100 ppm, less than about 90 ppm, less than about 80ppm, less than about 70 ppm, less than about 60 ppm, less than about 50ppm, less than about 40 ppm, less than about 30 ppm, or less than about20 ppm of the 14-hydroxymorphinone salt or solvate thereof (HPLC peakarea ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 10 ppm, less than about 8 ppm, less than about 6 ppm,less than about 4 ppm, or less than about 2 ppm of the14-hydroxymorphinone salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofis less than about 1 ppm, less than about 0.8 ppm, less than about 0.6ppm, less than about 0.4 ppm, less than about 0.3 ppm, less than about0.2 ppm, or less than about 0.1 ppm of the 14-hydroxymorphinone salt orsolvate thereof (e.g., the amount of 8-hydroxyoxymorphone is from about0.05 ppm to about 0.7 ppm of the 14-hydroxymorphinone sulfate) (HPLCpeak area ratio).

In certain embodiments, the 14-hydroxymorphinone salt or solvate thereofdoes not contain 8-hydroxyoxymorphone.

In certain embodiments, the 14-hydroxymorphinone salt is14-hydroxymorphinone sulfate, and the amount of 8-hydroxyoxymorphonetherein is less than about 300 ppm, less than about 275 ppm, less thanabout 250 ppm, less than about 225 ppm, less than about 200 ppm, lessthan about 175 ppm, less than about 150 ppm, less than about 125 ppm,less than about 100 ppm, less than about 80 ppm, less than about 60 ppm,less than about 40 ppm, less than about 30 ppm, or less than about 20ppm of the 14-hydroxymorphinone sulfate (HPLC peak area ratio). Incertain embodiments, it is less than about 10 ppm, less than about 8ppm, less than about 6 ppm, less than about 4 ppm, less than about 2ppm, less than about 1 ppm, less than about 0.8 ppm, less than about 0.6ppm, less than about 0.4 ppm, less than about 0.3 ppm, less than about0.2 ppm, or less than about 0.1 ppm of the 14-hydroxymorphinone sulfate(HPLC peak area ratio). In certain embodiments, the 14-hydroxymorphinonesulfate does not contain 8-hydroxyoxymorphone.

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the 14-hydroxymorphinone salt or solvate thereofhas a lower limit of about 0.01 ppm of the 14-hydroxymorphinone salt orsolvate thereof (HPLC peak area ratio). In certain embodiments, thelower limit is about 0.05 ppm, 0.1 ppm, about 0.3 ppm, about 0.5 ppm,about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or about 3 ppm.For example, the amount of the 8-hydroxyoxymorphone or salt or solvatethereof in the 14-hydroxymorphinone salt or solvate thereof may rangefrom about 0.05 ppm to 1 ppm in a certain embodiment, and from about 1ppm to about 10 ppm in a certain other embodiment.

The 14-hydroxymorphinone salt or solvate thereof in certain embodimentscomprises from about 0.01 ppm to about 2500 ppm, from about 0.05 toabout 2250 ppm, from about 0.1 ppm to about 2000 ppm, from about 0.3 toabout 1750 ppm, from about 0.5 ppm to about 1500 ppm, or from about 1ppm to about 1250 ppm 8-hydroxyoxymorphone or a salt or solvate thereofin relation to the 14-hydroxymorphinone salt (HPLC peak area ratio).

The 14-hydroxymorphinone salt or solvate thereof in certain embodimentscomprises from about 0.05 ppm to about 1000 ppm, from about 0.1 ppm toabout 800 ppm, from about 0.1 ppm to about 700 ppm, from about 0.2 ppmto about 600 ppm, from about 0.3 ppm to about 500 ppm, or from about 0.5ppm to about 400 ppm 8-hydroxyoxymorphone or salt or solvate thereof inrelation to the 14-hydroxymorphinone salt.

The 14-hydroxymorphinone salt or solvate thereof in certain embodimentscomprises from about 0.05 ppm to about 350 ppm, from about 0.1 ppm toabout 300 ppm, from about 0.2 ppm to about 275 ppm, from about 0.3 ppmto about 250 ppm, from about 0.4 ppm to about 225 ppm, or from about 0.5ppm to about 200 ppm 8-hydroxyoxymorphone or salt or solvate thereof inrelation to the 14-hydroxymorphinone salt.

The 14-hydroxymorphinone salt may comprise the 8-hydroxyoxymorphone as(i) 8α isomer, (ii) 8β isomer or (iii) a combination of 8α and 8βisomer. Preferably, at least a portion of the 8-hydroxyoxymorphone isthe 8α isomer.

Preferably, the 14-hydroxymorphinone salt is 14-hydroxymorphinonesulfate.

VI. Oxymorphone

Present invention further provides oxymorphone or a salt or solvatethereof, which is obtainable or preferably has been obtained by thehydrogenation process according to the present invention.

The salt or solvate of the oxymorphone may be a pharmaceuticallyacceptable salt or solvate. Such salts or solvates are known in the art.

The oxymorphone according to the present invention is preferably in itsfree base form or in the form of a solvate thereof.

The oxymorphone according to the present invention may be comprised in acomposition, which may be a solid or a liquid. Said composition may theproduct of the hydrogenation process according to the present invention.

In certain embodiments, the oxymorphone is a solid. In certainembodiments, it is the precipitate containing the oxymorphone base asdescribed as product of the hydrogenation process described in SectionII.

The oxymorphone or the (optionally pharmaceutically acceptable) salt orsolvate thereof in certain embodiments comprises 8-hydroxyoxymorphone.

Preferably, the oxymorphone or the (optionally pharmaceuticallyacceptable) salt or solvate thereof contains less than about 5 ppm, morepreferably less than about 3 ppm, even more preferably less than about 1ppm 8-hydroxyoxymorphone (HPLC peak area ratio). Most preferably, itdoes not contain 8-hydroxyoxymorphone in detectable amounts, and evenmay not contain any 8-hydroxyoxymorphone at all.

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about2500 ppm, less than about 2250 ppm, less than about 2000 ppm, less thanabout 1750 ppm, less than about 1500 ppm, or less than about 1250 ppm ofthe oxymorphone or salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about1000 ppm, less than about 750 ppm, less than about 500 ppm, or less thanabout 400 ppm of the oxymorphone or salt or solvate thereof (HPLC peakarea ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about300 ppm, less than about 275 ppm, less than about 250 ppm, less thanabout 225 ppm, less than about 200 ppm, less than about 175 ppm, lessthan about 150 ppm, or less than about 125 ppm of the oxymorphone orsalt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about100 ppm, less than about 90 ppm, less than about 80 ppm, less than about70 ppm, less than about 60 ppm, less than about 50 ppm, less than about40 ppm, less than about 30 ppm, or less than about 20 ppm of theoxymorphone or salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about10 ppm, less than about 8 ppm, less than about 6 ppm, less than about 4ppm, or less than about 2 ppm of the oxymorphone or salt or solvatethereof (HPLC peak area ratio).

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about1 ppm, less than about 0.8 ppm, less than about 0.6 ppm, less than about0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less thanabout 0.1 ppm of the oxymorphone or salt or solvate thereof (e.g., theamount of 8-hydroxyoxymorphone is from about 0.1 ppm to about 0.7 ppm ofthe 14-hydroxymorphinone sulfate) (HPLC peak area ratio).

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof does not contain8-hydroxyoxymorphone in detectable amounts, or not contain any8-hydroxyoxymorphone.

In certain embodiments, the amount of the 8-hydroxyoxymorphone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof has a lower limitof about 0.05 ppm of the oxymorphone or salt or solvate thereof (HPLCpeak area ratio). In certain embodiments, the lower limit is about 0.1ppm, about 0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5ppm, about 2 ppm, or about 3 ppm. For example, the amount of the8-hydroxyoxymorphone or salt or solvate thereof in the composition mayrange from about 0.05 ppm to 1 ppm in a certain embodiment, and fromabout 1 ppm to about 10 ppm in a certain other embodiment.

In certain embodiments, the amount of 8-hydroxyoxymorphone or salt orsolvate thereof in the oxymorphone or the salt or solvate thereof isless than about 300 ppm, less than about 275 ppm, less than about 250ppm, less than about 225 ppm, less than about 200 ppm, less than about175 ppm, less than about 150 ppm, less than about 125 ppm, less thanabout 100 ppm, less than about 80 ppm, less than about 60 ppm, less thanabout 40 ppm, less than about 30 ppm, or less than about 20 ppm of theoxymorphone (HPLC peak area ratio). In certain embodiments, it is lessthan about 10 ppm, less than about 8 ppm, less than about 6 ppm, lessthan about 4 ppm, less than about 2 ppm, less than about 1 ppm, lessthan about 0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm,less than about 0.3 ppm, less than about 0.2 ppm, or less than about 0.1ppm of the oxymorphone (HPLC peak area ratio). In certain embodiments,the oxymorphone does not contain 8-hydroxyoxymorphone.

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises fromabout 0.05 ppm to about 2500 ppm, from about 0.05 to about 2250 ppm,from about 0.1 ppm to about 2000 ppm, from about 0.3 to about 1750 ppm,from about 0.5 ppm to about 1500 ppm, or from about 1 ppm to about 1250ppm 8-hydroxyoxymorphone or a salt or solvate thereof in relation to theoxymorphone or salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises fromabout 0.05 ppm to about 1000 ppm, from about 0.1 ppm to about 800 ppm,from about 0.1 ppm to about 700 ppm, from about 0.2 ppm to about 600ppm, from about 0.3 ppm to about 500 ppm, or from about 0.5 ppm to about400 ppm 8-hydroxyoxymorphone or salt or solvate thereof in relation tothe oxymorphone or salt or solvate thereof.

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises fromabout 0.05 ppm to about 350 ppm, from about 0.1 ppm to about 300 ppm,from about 0.2 ppm to about 275 ppm, from about 0.3 ppm to about 250ppm, from about 0.4 ppm to about 225 ppm, or from about 0.5 ppm to about200 ppm 8-hydroxyoxymorphone or salt or solvate thereof in relation tocompound IV or salt or solvate thereof.

Additionally, the composition comprising the oxymorphone or the(optionally pharmaceutically acceptable) salt or solvate thereof incertain embodiments comprises 14-hydroxymorphinone.

Preferably, the oxymorphone or the (optionally pharmaceuticallyacceptable) salt or solvate thereof contains less than about 5 ppm, morepreferably less than about 3 ppm, even more preferably less than about 1ppm 14-hydroxymorphinone (HPLC peak area ratio). Most preferably, itdoes not contain 14-hydroxymorphinone in detectable amounts, and evenmay not contain any 14-hydroxymorphinone at all.

The amount of the 14-hydroxymorphinone or salt or solvate thereof inrelation to the amount of the oxymorphone or salt or solvate thereof mayin certain embodiments be less than about 500 ppm, less than about 250ppm, less than about 200 ppm, less than about 100 ppm, less than about50 ppm or less than about 40 ppm (HPLC peak area ratio). In certainembodiments, it may be less than about 30 ppm, less than about 25 ppm,less than about 20 ppm, les than about 15 ppm, less than about 10 ppm,less than about 5 ppm, or less than about 2.5 ppm (HPLC peak arearatio). In certain embodiments, it may be less than about 1 ppm, lessthan about 0.8 ppm, less than about 0.6 ppm, less than about 0.6 ppm,less than about 0.4 ppm, less than about 0.2 ppm, or less than about 0.1ppm (HPLC peak area ratio). In certain embodiments, the oxymorphone orthe (optionally pharmaceutically acceptable) salt or solvate thereofdoes not contain 14-hydroxymorphinone (in detectable amounts).

In certain embodiments, the amount of the 14-hydroxymorphinone or saltor solvate thereof in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof has a lower limitof about 0.05 ppm of the oxymorphone or salt or solvate thereof (HPLCpeak area ratio). In certain embodiments, the lower limit is about 0.1ppm, about 0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5ppm, about 2 ppm, or about 3 ppm. For example, the amount of the14-hydroxymorphinone or salt or solvate thereof in the oxymorphone orthe (optionally pharmaceutically acceptable) salt or solvate thereof mayrange from about 0.05 ppm to 1 ppm in a certain embodiment, and fromabout 1 ppm to about 10 ppm in a certain other embodiment.

The oxymorphone or the (optionally pharmaceutically acceptable) salt orsolvate thereof in certain embodiments comprises from about 0.05 ppm toabout 500 ppm, from about 0.05 ppm to about 250 ppm, from about 0.05 ppmto about 200 ppm, from about 0.05 ppm to about 100 ppm, from about 0.05ppm to about 50 ppm, from about 0.05 ppm to about 25 ppm, from about0.05 ppm to about 10 ppm, from about 0.05 ppm to about 5 ppm, or fromabout 0.05 ppm to about 1 ppm 14-hydroxymorphinone or salt or solvatethereof in relation to oxymorphone or the salt or solvate thereof.

In certain embodiments, the amount of the 14-hydroxymorphinone inrelation to the amount of the oxymorphone in the oxymorphone or the saltor solvate thereof is less than about 200 ppm, less than about 175 ppm,less than about 150 ppm, less than about 125 ppm, less than about 100ppm, less than about 80 ppm, less than about 60 ppm, less than about 40ppm, less than about 30 ppm, less than about 20 ppm, or less than about10 ppm, or less than about 5 ppm of the oxymorphone (HPLC peak arearatio). In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof does not contain14-hydroxymorphinone or a salt or solvate thereof.

The oxymorphone or salt or solvate thereof may also additionallycomprise a combination of 14-hydroxymorphinone with8-hydroxyoxymorphone, preferably within the limits for the singlecompounds 8-hydroxyoxymorphone and 14-hydroxymorphinone as described inthe preceding paragraphs.

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof additionallycomprises both 14-hydroxymorphinone and 8-hydroxyoxymorphone. In certainembodiments, the oxymorphone or the (optionally pharmaceuticallyacceptable) salt or solvate thereof comprises a combined amount of14-hydroxymorphinone and 8-hydroxyoxymorphone which is less than about1000 ppm, less than about 750 ppm, less than about 500 ppm, less thanabout 400 ppm, less than about 300 ppm, or less than about 275 ppm inrelation to the amount of the oxymorphone (HPLC peak area ratio).

In certain embodiments, the combined amount of the compound14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or the(optionally pharmaceutically acceptable) salt or solvate thereof is lessthan about 250 ppm, less than about 225 ppm, less than about 200 ppm,less than about 175 ppm, less than about 150 ppm, or less than about 125ppm in relation to the amount of the oxymorphone (HPLC peak area ratio).

In certain embodiments, the combined amount of the 14-hydroxymorphinoneand 8-hydroxyoxymorphone in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about100 ppm, less than about 90 ppm, less than about 80 ppm, less than about70 ppm, less than about 60 ppm, less than about 50 ppm, less than about40 ppm, less than about 30 ppm, or less than about 20 ppm in relation tothe amount of the oxymorphone (HPLC peak area ratio).

In certain embodiments, the combined amount of the 14-hydroxymorphinoneand 8-hydroxyoxymorphone in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about10 ppm, les than about 8 ppm, less than about 6 ppm, less than about 4ppm, or less than about 2 ppm in relation to the amount of theoxymorphone (HPLC peak area ratio).

In certain embodiments, the combined amount of the 14-hydroxymorphinoneand 8-hydroxyoxymorphone in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof is less than about1 ppm, less than about 0.8 ppm, less than about 0.6 ppm, less than about0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less thanabout 0.1 ppm in relation to the amount of the oxymorphone (HPLC peakarea ratio).

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof does not contain14-hydroxymorphinone and 8-hydroxyoxymorphone (in detectable amounts).

Preferably, the oxymorphone or the (optionally pharmaceuticallyacceptable) salt or solvate thereof contains less than about 10 ppm,more preferably less than about 6 ppm, even more preferably less thanabout 4 ppm combined 14-hydroxymorphinone and 8-hydroxyoxymorphone (HPLCpeak area ratio). Most preferably, it does not contain14-hydroxymorphinone and 8-hydroxyoxymorphone in detectable amounts, andeven may not contain any 14-hydroxymorphinone and 8-hydroxyoxymorphoneat all.

In certain embodiments, the combined amount of the 14-hydroxymorphinoneand 8-hydroxyoxymorphone in the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof has a lower limitof about 0.05 ppm of the oxymorphone (HPLC peak area ratio). In certainembodiments, the lower limit is about 0.1 ppm, about 0.3 ppm, about 0.5ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or about 3ppm in relation to the amount of the oxymorphone (HPLC peak area ratio).

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises less thanabout 200 ppm, less than about 100 ppm, less than about 50 ppm, lessthan about 25 ppm, less than about 20 ppm, less than about 15 ppm, orless than about 10 ppm of 14-hydroxymorphinone or a salt or solvatethereof, and/or less than about 300 ppm, less than about 200 ppm, lessthan about 100 ppm, less than about 50 ppm, less than about 25 ppm, orless than about 10 ppm of 8-hydroxyoxymorphone or a salt or solvatethereof.

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises less thanabout 25 ppm, less than about 20 ppm, less than about 15 ppm, less thanabout 10 ppm, less than about 5 ppm, or less than about 1 ppm of14-hydroxymorphinone or a salt or solvate thereof, and/or less thanabout 100 ppm, less than about 50 ppm, less than about 25 ppm, less thanabout 10 ppm, or less than about 5 ppm of 8-hydroxyoxymorphone or a saltor solvate thereof.

In certain embodiments, the oxymorphone or the (optionallypharmaceutically acceptable) salt or solvate thereof comprises less thanabout 10 ppm, less than about 5 ppm, less than about 4 ppm, less thanabout 3 ppm, less than about 2 ppm, less than about 1 ppm, or less thanabout 0.5 ppm of 14-hydroxymorphinone or a salt or solvate thereof,and/or less than about 10 ppm, less than about 5 ppm, less than about 3ppm, less than about 2 ppm, less than about 1 ppm, or less than about0.5 ppm of 8-hydroxyoxymorphone or a salt or solvate thereof.

In certain embodiments, the oxymorphone or a salt or solvate thereofadditionally comprises (i) 8-hydroxyoxymorphone or a salt or solvatethereof, and/or (ii) 14-hydroxymorphinone or a salt or solvate thereof,wherein the amount of the 8-hydroxyoxymorphone is less than about 300ppm, less than about 275 ppm, less than about 250 ppm, less than about225 ppm, less than about 200 ppm, less than about 175 ppm, less thanabout 150 ppm, less than about 125 ppm, less than about 100 ppm, lessthan about 80 ppm, less than about 60 ppm, less than about 40 ppm, lessthan about 30 ppm, less than about 20 ppm, less than about 10 ppm, lessthan about 8 ppm, less than about 6 ppm, less than about 4 ppm, lessthan about 2 ppm, less than about 1 ppm, less than about 0.8 ppm, lessthan about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm,less than about 0.2 ppm, or less than about 0.1 ppm of the oxymorphone(HPLC peak area ratio; e.g., from about 0.2 ppm to about 50 ppm of theoxymorphone), and the amount of the 14-hydroxymorphinone is less thanabout 200 ppm, less than about 175 ppm, less than about 150 ppm, lessthan about 125 ppm, less than about 100 ppm, less than about 80 ppm,less than about 60 ppm, less than about 40 ppm, less than about 30 ppm,less than about 20 ppm, or less than about 10 ppm, or less than about 5ppm of the oxymorphone (HPLC peak area ratio; e.g., from about 0.1 ppmto about 15 ppm, or from about 0.2 ppm to about 2 ppm of theoxymorphone). In preferred embodiments, the oxymorphone is oxymorphonefree base.

In certain embodiments, the oxymorphone is oxymorphone free base andadditionally comprises (i) 8-hydroxyoxymorphone or a salt or solvatethereof, and/or (ii) 14-hydroxymorphinone or a salt or solvate thereof,wherein the amount of the 8-hydroxyoxymorphone is less than about 100ppm, less than about 80 ppm, less than about 60 ppm, less than about 40ppm, less than about 30 ppm, less than about 20 ppm, less than about 10ppm, less than about 5 ppm, or less than about 2 ppm of the oxymorphonesalt (HPLC peak area ratio; e.g., from about 0.1 ppm to about 9 ppm ofthe oxymorphone salt), and the amount of the 14-hydroxymorphinone isless than about 50 ppm, less than about 25 ppm, less than about 10 ppm,less than about 5 ppm, or less than about 2 ppm of the oxymorphone salt(HPLC peak area ratio).

VII. Use of the Oxymorphone

VII-A. Use in a Medicament

Oxymorphone or a pharmaceutically acceptable salt or solvate thereof canbe used as API of a medicament. To date, the API form of oxymorphone isoxymorphone hydrochloride.

For this use, the oxymorphone or the pharmaceutically acceptable salt orsolvate thereof may be the oxymorphone as described in Section VI.

For this use, the oxymorphone or the pharmaceutically acceptable salt orsolvate thereof may be used in a dosage form as described in SectionVIII.

In the context of the present invention, the oxymorphone is preferablyprepared as its free base according to the process of the presentinvention, and then used either directly as API, or converted into apharmaceutically acceptable salt or solvate which is then used as API,in particular, oxymorphone hydrochloride.

For this use, the medicament may be for treating a medical conditionselected from the group consisting of pain, addiction, cough,constipation, diarrhea, insomnia associated with and/or caused by pain,cough or addiction, depression associated with and/or resulting frompain, cough or addiction, or a combination of two or more of theforegoing conditions. In particular, said condition may be pain.

The present invention also provides a method for treating an animal,preferably a mammal (e.g., a human), (in the following: “a patient”)using the oxymorphone or a pharmaceutically acceptable salt or solvatethereof. Said treatment may be of any medical condition which isconventionally treated by administration of oxymorphone or apharmaceutically acceptable salt or solvate thereof to a patient.

Said medical condition may be pain, addiction, cough, constipation,diarrhea, insomnia associated with and/or caused by pain, cough oraddiction, depression associated with and/or resulting from pain, coughor addiction, or a combination of two or more of the foregoingconditions. In particular, said condition may be pain.

For this method of treatment, the oxymorphone or the pharmaceuticallyacceptable salt or solvate thereof may be the compound as described inSection VI.

For this method of treatment, the oxymorphone or the pharmaceuticallyacceptable salt or solvate thereof may be used in a dosage form asdescribed in Section VIII.

VII-B. Other Uses

The oxymorphone (prepared) according to the present invention or an(optionally pharmaceutically acceptable) salt or solvate thereof mayalso be used as follows:

In certain embodiments, the oxymorphone or (optionally pharmaceuticallyacceptable) salt or solvate thereof is used as an intermediate orstarting material for preparing the oxymorphone in its free base form orfor preparing another salt or solvate of oxymorphone, e.g., forpreparing a(nother) pharmaceutically acceptable salt or solvate ofoxymorphone. For example, the oxymorphone may be used for preparingoxymorphone hydrochloride. Processes for preparing said other salt orsolvate which involve a process or compound as described above in thedetailed description are also embodiments of the present invention.

In certain embodiments, the oxymorphone or (optionally pharmaceuticallyacceptable) salt or solvate thereof is used as an intermediate orstarting material for preparing another opioid or a pharmaceuticallyacceptable salt or solvate thereof or a prodrug thereof, and/or forpreparing a medicament containing the oxymorphone or a pharmaceuticallyacceptable salt or solvate thereof, or containing another opioid or apharmaceutically acceptable salt or solvate thereof. For example,oxymorphone may be used as starting material for preparing oxycodone,naloxone, noroxymorphone, naltrexone, methyl naltrexone, nalmafine, ornalfurafine. Processes for preparing said other opioids which involve aprocess or compound as described above in the detailed description arealso embodiments of the present invention.

VIII. Dosage Forms

Dosage forms in accordance with the present invention comprise one ormore of the compounds described above and one or more pharmaceuticallyacceptable excipients. The dosage forms may or may not beabuse-resistant.

Those compounds, salts or solvates according to the present inventionwhich are or contain an active pharmaceutical ingredient, in particularthe oxymorphone which is described in Section VI, the pharmaceuticallyacceptable salts and solvates thereof, can be comprised in apharmaceutical dosage form or medicament. Other opioids made fromcompounds, salts or solvates according to the present invention can alsobe comprised in a pharmaceutical dosage form or medicament. Prodrugs ofthe opioids described herein can also be comprised in a pharmaceuticaldosage form or medicament. Such dosage forms and medicaments are also anembodiment of the present invention.

In addition to said active pharmaceutical ingredient, said dosage formscomprise one or more pharmaceutically acceptable excipients.

A pharmaceutical dosage form of the present invention may comprise (i)an opioid prepared according to present invention or a pharmaceuticallyacceptable salt or solvate thereof, and (ii) one or morepharmaceutically acceptable excipients. In particular, a pharmaceuticaldosage form of the present invention may comprise (i) oxymorphone or anoxymorphone salt or solvate as described above, and (ii) one or morepharmaceutically acceptable excipients.

In certain embodiments, the dosage form comprises oxymorphone or apharmaceutically acceptable salt or solvate thereof, wherein saidcompounds have the properties as described in Section VI and/or havebeen prepared according to a process of the present invention. In oneembodiment, the oxymorphone salt is oxymorphone hydrochloride.

In certain embodiments, the dosage form comprises a combination ofoxymorphone or a salt or solvate thereof which has the properties asdescribed in Section VI and/or has been prepared according to a processof the present invention, with another opioid. In certain embodiments,the dosage form comprises a combination of oxymorphone or a salt orsolvate thereof which has the properties as described in Section VIand/or has been prepared according to a process of the presentinvention, with an opioid receptor antagonist. For example, a dosageform of the present invention may comprise a combination of oxymorphoneor a pharmaceutically acceptable salt or solvate thereof (such asoxymorphone hydrochloride) and naloxone or a pharmaceutically acceptablesalt or solvate (such as naloxone hydrochloride).

In certain embodiments, the dosage form is selected from the groupconsisting of oral dosage forms (e.g., tablets, capsules, suspensions,solutions, etc.), injectable dosage forms, rectal dosage forms (e.g.,suppositories), and transdermal dosage forms (e.g., patches).

In certain embodiments, the pharmaceutical composition or dosage formdoes not contain 14-hydroxymorphinone and/or 8-hydroxyoxymorphone.Preferably, neither 14-hydroxymorphinone nor 8-hydroxyoxymorphone arecontained.

In said embodiments, the dosage form may be selected from the groupconsisting of oral dosage forms (e.g., tablets, capsules, suspensions,solutions, etc.), injectable dosage forms, rectal dosage forms (e.g.,suppositories), and transdermal dosage forms (e.g., patches). Dosageforms for oral administration may be presented as tablets, capsules,liquid formulations, troches, lozenges, powders, granules,microparticles (e.g., microcapsules, microspheres and the like), orbuccal tablets.

In certain embodiments, oral dosage forms of the present invention maybe in the form of tablets (sustained release and/or immediate release),solutions, suspensions, etc.

Oral dosage forms can provide a controlled release (sustained release ordelayed release) or an immediate release of the active pharmaceuticalingredient. One of the conventional excipients may be a pharmaceuticallyacceptable carrier. Suitable pharmaceutically acceptable carriersinclude but are not limited to, e.g., alcohols, gum arabic, vegetableoils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates suchas lactose, amylose or starch, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The dosage form may further comprise an inertdiluent such as lactose; granulating and disintegrating agents such ascornstarch; binding agents such as starch; and lubricating agents suchas magnesium stearate. The tablets may be uncoated or they may be coatedby known techniques for elegance or to provide a controlled release ofthe drug (a sustained release, a delayed release or a pulsatile release)of the pharmaceutical composition.

The pharmaceutical preparations can be sterilized and if desired mixedwith auxiliary agents, e.g., lubricants, disintegrants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike.

The compositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of the pharmaceutically acceptable dosage forms.

In certain embodiments, the sustained release dosage form may optionallycomprise particles containing an opioid pharmaceutical compositiondescribed above. In certain embodiments, the particles have a diameterfrom about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about2 mm. The particles may be film coated with a material that permitsrelease of the active at a sustained rate in an aqueous medium. The filmcoat may be chosen so as to achieve, in combination with the otheringredients of the dosage form, desired release properties. Thesustained release coating formulations of the present invention shouldbe capable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu panel 18/20 beads,and a plurality of the resultant solid sustained release beads maythereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective sustained release dose of the opioid pharmaceuticalcomposition when ingested and contacted by an environmental fluid, e.g.,gastric fluid or dissolution media.

The sustained release bead formulations of the present invention slowlyrelease the active of the present invention, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids.

The sustained release profile of the formulations of the invention canbe altered, for example, by varying the amount of overcoating with thehydrophobic material, altering the manner in which a plasticizer isadded to the hydrophobic material, by varying the amount of plasticizerrelative to hydrophobic material, by the inclusion of additionalingredients or excipients, by altering the method of manufacture, etc.

The dissolution profile of the ultimate product may also be modified,for example, by increasing or decreasing the thickness of the retardantcoating.

Spheroids or beads coated with the agent(s) of the present invention areprepared, e.g., by dissolving the pharmaceutical compositions in waterand then spraying the solution onto a substrate, for example, nu panel18/20 beads, using a Wurster insert. Optionally, additional ingredientsmay be added prior to coating the beads in order to assist the bindingof the pharmaceutical compositions to the beads, and/or to color thesolution, etc. For example, a product which includeshydroxypropylmethylcellulose, etc. with or without colorant (e.g.,Opadry®, commercially available from Colorcon, Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the active(s) from the hydrophobic sustained releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.,triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the agent(s) by spraying using any suitable spray equipmentknown in the art. In a preferred method, a Wurster fluidized-bed systemis used in which an air jet, injected from underneath, fluidizes thecore material and effects drying while the acrylic polymer coating issprayed on. A sufficient amount of the hydrophobic material to obtain apredetermined sustained release of the pharmaceutical composition whenthe coated substrate is exposed to aqueous solutions, e.g., gastricfluid, may be applied. After coating with the hydrophobic material, afurther overcoat of a film-former, such as, e.g., Opadry®, may beoptionally applied to the beads. This overcoat is provided, if at all,e.g., in order to substantially reduce agglomeration of the beads.

The release of the pharmaceutical composition(s) from the sustainedrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in an environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and 4,088,864.

Matrix Formulations

In other embodiments of the present invention, the sustained releaseformulation is achieved via a sustained release matrix optionally havinga sustained release coating as set forth herein. The materials suitablefor inclusion in the sustained release matrix may depend on the methodused to form the matrix.

For example, a matrix in addition to the pharmaceutical compositionsdescribed above may include hydrophilic and/or hydrophobic materials,such as gums, cellulose ethers, acrylic resins, protein derivedmaterials; the list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material or hydrophilic materialwhich is capable of imparting sustained release of the pharmaceuticalcomposition(s) and which melts (or softens to the extent necessary to beextruded) may be used in accordance with the present invention.

The oral dosage form may contain between 1% and 80% (by weight) of oneor more hydrophilic or hydrophobic material(s).

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing. Of thesematerials, acrylic polymers, e.g., Eudragit® RSPO, the cellulose ethers,e.g., hydroxyalkylcelluloses and carboxyalkylcelluloses are preferred.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 40° C. to about 200° C., preferably from about 45° C. to about 90°C. Specifically, the hydrophobic material may comprise natural orsynthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl,cetyl or preferably cetostearyl alcohol), fatty acids, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicacid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes are waxes as defined in Fette,Seifen, Anstrichmittel 76, 135 (1974) and include, for example, beeswax,glycowax, castor wax and carnauba wax.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andnatural and synthetic waxes. Hydrocarbons having a melting point ofbetween 25° C. and 90° C. are preferred. Of the long chain hydrocarbonmaterials, fatty (aliphatic) alcohols are preferred in certainembodiments. The oral dosage form may contain up to 60% of at least onelong chain hydrocarbon.

In certain embodiments, a combination of two or more hydrophobicmaterials is included in the matrix formulations. If an additionalhydrophobic material is included, it is preferably selected from naturaland synthetic waxes, fatty acids, fatty alcohols, and mixtures of thesame. Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate of APIrelease required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by weight) ofthe at least one aliphatic alcohol. When at least one polyalkyleneglycol is present in the oral dosage form, then the combined weight ofthe at least one aliphatic alcohol and the at least one polyalkyleneglycol preferably constitutes between 20% and 50% (by weight) of thetotal dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a (w/w) of the at least onehydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

In certain embodiments, the oral dosage form contains at least onepolyalkylene glycol. The amount of the at least one polyalkylene glycolin the oral dosage form may be up to 60%. The at least one polyalkyleneglycol may be, for example, polypropylene glycol or, which is preferred,polyethylene glycol. The number average molecular weight of the at leastone polyalkylene glycol is preferred between 1,000 and 15,000 especiallybetween 1,500 and 12,000.

In certain embodiments, the sustained release matrix may comprisepolyethylene oxide. In certain embodiments polyethylene oxide comprisesfrom about 40% to about 95% of the dosage form. In certain embodimentspolyethylene oxide comprises from about 50% to about 95% of the dosageform. In certain embodiments polyethylene oxide comprises from about 55%to about 90% of the dosage form. In certain embodiments polyethyleneoxide comprises from about 60% to about 90% of the dosage form.

Another suitable sustained release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Matrix-Particulates

In order to facilitate the preparation of a solid, sustained release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose, and an opioid according to present invention; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂-C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose granules with water.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active can be spheronized to form spheroids. Microcrystallinecellulose is a preferred spheronizing agent. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, is preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic material, e.g., a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g., ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w). For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about25° to about 100° C.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g., diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% of theparticulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986).

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theAPI together with at least one hydrophobic material and preferably theadditional hydrophobic material to obtain a homogeneous mixture. Thehomogeneous mixture is then heated to a temperature sufficient to atleast soften the mixture sufficiently to extrude the same. The resultinghomogeneous mixture is then extruded to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The strands are cooled and cut into multiparticulates. Themultiparticulates are then divided into unit doses. The extrudatepreferably has a diameter of from about 0.1 to about 5 mm and providessustained release of the API for a time period of from about 8 to about24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, the opioid API, and an optional binder; heating the homogenousmixture; extruding the homogenous mixture to thereby form strands;cooling the strands containing the homogeneous mixture; cutting thestrands into particles having a size from about 0.1 mm to about 12 mm;and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule containing themultiparticulates can be further coated, with a sustained releasecoating such as the sustained release coatings described above. Suchcoatings preferably include a sufficient amount of hydrophobic materialto obtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the desired release rate,among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded particles before beingencapsulated. Furthermore, the unit dosage forms can also include anamount of an immediate release agent for prompt release. The immediaterelease agent may be incorporated, e.g., as separate pellets within agelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g., sustainedrelease coating or matrix-based). The unit dosage forms of the presentinvention may also contain a combination of sustained release beads andmatrix multiparticulates to achieve a desired effect.

The sustained release formulations of the present invention preferablyslowly release the agent(s), e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The sustained release profile ofthe melt-extruded formulations of the invention can be altered, forexample, by varying the amount of retardant, i.e., hydrophobic material,by varying the amount of plasticizer relative to hydrophobic material,by the inclusion of additional ingredients or excipients, by alteringthe method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the API, which can be added thereafterto the extrudate. Such formulations typically will have the agentsblended together with the extruded matrix material, and then the mixturewould be tableted in order to provide a slow release formulation.

Coatings

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release. A pH-dependentcoating serves to release the active in desired areas of thegastro-intestinal (GI) tract, e.g., the stomach or small intestine, suchthat an absorption profile is provided which is capable of providing atleast about eight hours and preferably about twelve hours to up to abouttwenty-four hours of the therapeutic effect (such as analgesia) to apatient. When a pH-independent coating is desired, the coating isdesigned to achieve optimal release regardless of pH-changes in theenvironmental fluid, e.g., the GI tract. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the API is coated with a hydrophobicmaterial selected from (i) an alkylcellulose; (ii) an acrylic polymer;or (iii) mixtures thereof. The coating may be applied in the form of anorganic or aqueous solution or dispersion. The coating may be applied toobtain a weight gain from about 2 to about 25% of the substrate in orderto obtain a desired sustained release profile. Coatings derived fromaqueous dispersions are described, e.g., in detail in U.S. Pat. Nos.5,273,760 and 5,286,493.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include those describedin U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the sustained release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, amino alkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Evonik. Thereare several different types of Eudragit®. For example, Eudragit® E is anexample of a methacrylic acid copolymer which swells and dissolves inacidic media. Eudragit® L is a methacrylic acid copolymer which does notswell at about pH<5.7 and is soluble at about pH>6. Eudragit® S does notswell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Evonikunder the trade names Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions may be mixed together in any desiredratio in order to ultimately obtain a sustained release formulationhaving a desirable dissolution profile. Desirable sustained releaseformulations may be obtained, for instance, from a retardant coatingderived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS,and 10% Eudragit® RL and 90% Eudragit® RS. Of course, one skilled in theart will recognize that other acrylic polymers may also be used, suchas, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethyl-cellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent of the film-former. Concentration of the plasticizer,however, can only be properly determined after careful experimentationwith the particular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Sustained Release Osmotic Dosage Form

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer (e.g.,containing oxymorphone or a salt or solvate thereof as described above)and a delivery or push layer, wherein the bilayer core is surrounded bya semipermeable wall and optionally having at least one passagewaydisposed therein.

The expression “passageway” as used for the purpose of the presentdescription, includes aperture, orifice, bore, pore, porous elementthrough which an API (e.g., oxymorphone hydrochloride) may be pumped,diffuse or migrate through a fiber, capillary tube, porous overlay,porous insert, microporous member, or porous composition. The passagewaycan also include a compound that erodes or is leached from the wall inthe fluid environment of use to produce at least one passageway.Representative compounds for forming a passageway include erodiblepoly(glycolic) acid, or poly(lactic) acid in the wall; a gelatinousfilament; a water-removable poly(vinyl alcohol); leachable compoundssuch as fluid-removable pore-forming polysaccharides, acids, salts oroxides. A passageway can be formed by leaching a compound from the wall,such as sorbitol, sucrose, lactose, maltose, or fructose, to form asustained-release dimensional pore-passageway. The dosage form can bemanufactured with one or more passageways in spaced-apart relation onone or more surfaces of the dosage form. A passageway and equipment forforming a passageway are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064 and 4,088,864. Passageways comprisingsustained-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa sustained-release rate are disclosed in U.S. Pat. Nos. 4,200,098 and4,285,987.

In certain embodiments the drug layer may also comprise at least onepolymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅).H₂O, wherein n is 3 to 7,500, and themaltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of the osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the active pharmaceutical ingredient (e.g.,oxymorphone hydrochloride) from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkylcellulose is represented by a member selected from thegroup consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropyl isopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-di-tert butylphenol, α-tocopherol, and propylgallate.

In certain alternative embodiments, the dosage form comprises ahomogenous core comprising an active pharmaceutical ingredient (e.g.,oxymorphone hydrochloride), a pharmaceutically acceptable polymer (e.g.,polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thehomogenous core is surrounded by a semipermeable wall having apassageway (as defined above) for the release of the opioid API.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of from 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Suppositories

The sustained release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising a suitable suppository base, and a pharmaceutical opioidcomposition. Preparation of sustained release suppository formulationsis described in, e.g., U.S. Pat. No. 5,215,758.

Prior to absorption, the drug must be in solution. In the case ofsuppositories, solution must be preceded by dissolution of thesuppository base, or the melting of the base and subsequent partition ofthe drug from the suppository base into the rectal fluid. The absorptionof the drug into the body may be altered by the suppository base. Thus,the particular suppository base to be used in conjunction with aparticular drug must be chosen giving consideration to the physicalproperties of the drug. For example, lipid-soluble drugs will notpartition readily into the rectal fluid, but drugs that are onlyslightly soluble in the lipid base will partition readily into therectal fluid.

Among the different factors affecting the dissolution time (or releaserate) of the drugs are the surface area of the drug substance presentedto the dissolution solvent medium, the pH of the solution, thesolubility of the substance in the specific solvent medium, and thedriving forces of the saturation concentration of dissolved materials inthe solvent medium. Generally, factors affecting the absorption of drugsfrom suppositories administered rectally include suppository vehicle,absorption site pH, drug pKa, degree of ionization, and lipidsolubility.

The suppository base chosen should be compatible with the active of thepresent invention. Further, the suppository base is preferably non-toxicand nonirritating to mucous membranes, melts or dissolves in rectalfluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B,BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent of the total weight ofthe suppository. Preferably, the amount of suppository base in thesuppository is from about 65 percent to about 80 percent, of the totalweight of the suppository.

The following examples are meant to illustrate, but in no way to limit,the present invention.

EXAMPLES Comparative Example 1 Preparation of Oxymorphone According toExample 2 of WO 2008/130553

Example 2 from WO 2008/130553 was repeated as follows.

1. Into a 100 mL reaction vessel equipped with a temperature probe, anoverhead stirrer and a reflux condenser, oripavine (3.03 g, 10.2 mmol)was charged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the reactionmixture. Upon the addition, the solids readily dissolved into solution.During the formic acid addition, the temperature of the reaction mixtureincreased to 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours, untilabout 95% of the oripavine had been consumed according to the HPLCanalysis described in Example 11A.

6. 0.30 g of 5% palladium on carbon was charged into the reactionmixture, and the mixture was stirred at 20° C. for 30 minutes.

7. Sodium formate (0.60 g, 8.82 mmol) and triethylamine (7.5 mL, 53.8mmol) were added to the reaction mixture, and the mixture was heated to45° C. and stirred at 45° C. for 2 hours.

8. The mixture was heated to 80° C. and stirred at 80° C. for anadditional 8 hours.

9. The reaction was then cooled to 20° C. and stirred at 20° C. for 8hours. No precipitation was observed at this temperature.

10. The reaction mixture was filtered through a plug of celite.

11. The filtrate was basified to a pH of about 9.3 with concentratedammonium hydroxide, to precipitate oxymorphone free base.

12. The resulting mixture was stirred at room temperature for 1 hour.

13. The resulting mixture was then filtered, washed with water (3×15mL), and dried in a vacuum oven at 80° C. for 16 hours to yield 2.04 gof solid.

14. Analysis of the solid by the HPLC method of Example 11A showed anHPLC peak area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of15,803,069:1,845:25,714. The oxymorphone base comprised 96.03% of thecomposition (based on HPLC area percent), 14-hydroxymorphinone comprised117 ppm of the composition (based on HPLC area percent), and8-hydroxyoxymorphone comprised 1627 ppm of the composition (based onHPLC area percent). The auto-scaled chromatogram and peak results fromthis analysis are depicted in FIG. 1.

About 14.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example (13.7 molar equivalents of HCO₂H,0.81 molar equivalents of H₂SO₄). The molar ratio of sulfuric acid toformic acid was about 1:17.2. No precipitation was observed up to step11. A molar excess of formic acid was present during the hydrogenation.

Comparative Example 2 Preparation of Oxymorphone Free Base According toExample 3 of WO 2008/130553

Example 3 from WO 2008/130553 was repeated as follows.

1. Into a 100 mL reaction vessel equipped with a temperature probe,overhead stirrer and reflux condenser, oripavine (3.01 g, 10.1 mmol) wascharged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the reaction. Uponthe addition, the solids readily dissolved into solution. During theformic acid addition, the temperature of the reaction mixture increasedto 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours, until theoripavine had been consumed according to the HPLC analysis of Example11A.

6. 0.30 g of 5% palladium on carbon was charged into the reactionmixture, and the mixture was stirred at 20° C. for 30 minutes.

7. Triethylamine (8.8 mL, 63.1 mmol) was added to the reaction mixture,and the reaction mixture was heated to 45° C. and stirred at 45° C. for2 hours.

8. The mixture was heated to 80° C. and stirred at 80° C. for anadditional 8 hours.

9. The reaction was then cooled to 20° C. and stirred at 20° C. for 8hours. No solid precipitation was observed at this temperature.

10. The reaction mixture was filtered through a plug of celite.

11. The filtrate was basified to pH=9.25 with concentrated ammoniumhydroxide, and the precipitated composition was allowed to stir at roomtemperature for 1 hour.

12. The precipitated composition was then filtered, washed with water(3×15 mL) and dried in a vacuum oven at 80° C. for 16 hours to yield1.33 g of precipitate.

13. Analysis of the precipitate by the HPLC method of Example 11A showedan HPLC peak area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of13,906,304:2,146:46,937. In other words, the oxymorphone base comprised94.94% of the composition (based on HPLC area percent),14-hydroxymorphinone comprised 154 ppm of the composition (based on HPLCarea percent), and 8-hydroxyoxymorphone comprised 3377 ppm of thecomposition (based on HPLC area percent). The auto-scaled chromatogramand peak results from this analysis are depicted in FIG. 2.

About 14.7 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:17.2. No precipitation was observed up to step11. A molar excess of formic acid was present during the hydrogenation.

Comparative Example 3 Preparation of 14-Hydroxymorphinone from OripavineWithout Sulfuric Acid

1. Oripavine (99.99 g, 336 mmol) was charged as a slurry in deionizedwater (150 mL) into a 500 mL jacketed vessel.

2. The slurry was stirred (250 rpm) at ambient reaction temperature(approximately 25° C.).

3. Formic acid (100 mL, 2332 mmol, 88%) was added to the mixture in oneportion. The solids completely dissolved upon the addition, and a slightexothermic reaction was observed (temperature increase to approximately34° C.). The solution was then allowed to cool back to ambienttemperature (approximately 25° C.).

4. While holding the temperature at approximately 25° C., hydrogenperoxide (31.2 mL, 363 mmol, 35%, M=11.86) was added to the solution ata controlled rate of 1.56 mL/minute (0.05 equivalents/minute).

5. After addition was complete, the solution was allowed to stir anadditional 30 minutes at ambient temperature.

6. The solution was then heated to 48° C. and held at this temperaturefor about 3.5 hours, and sampled by HPLC for reaction completion.

7. After approximately 3.5 hours of stirring at 48° C., the solution wascooled to 10° C. over 35 minutes.

8. The solution was held at 10° C. for approximately 16 hours, andanalyzed by HPLC. A sample was shown to contain 97.04% (based on HPLCarea percent) 14-hydroxymorphinone, 5200 ppm (based on HPLC areapercent) oripavine, and 10900 ppm (based on HPLC area percent)8-hydroxyoxymorphone.

9. The solution was then utilized for subsequent hydrogenation inExample 4.

Comparative Example 4 Preparation of Oxymorphone from14-Hydroxymorphinone

1. 5% Palladium on carbon (0.60 g) was charged into a 1 L ZipperClave®autoclave high pressure reaction vessel, followed by the solutionprepared in Example 3.

2. Deionized water (100 mL) and formic acid (100 mL, 88%, 2332 mmol)were added into the reaction solution in one portion.

3. The vessel was sealed and hydrogenated at 60 psia (413.69 kPa), 55°C., for 3 hours and 10 minutes.

4. The solution was vented and purged with nitrogen 3 times.

5. A sample of the solution was analyzed by HPLC for reactioncompletion.

6. The palladium on carbon was removed from the solution by filtrationthrough 2 layers of filter paper and the filtrate was stored in arefrigerator at approximately 5° C. overnight.

7. The filtrate was transferred to a cooled 1 L jacketed vessel (0-5°C.).

8. 50% sodium hydroxide was added into the cooled solution at a ratesuch that the temperature of the solution did not exceed 20° C., until afinal pH in a range from 9.0 to 9.25 was achieved.

9. The resulting solids were stirred at 5° C. for an additional 30minutes before being filtered by vacuum filtration through a paperfilter (Whatman#2).

10. The resulting solid material was slurry washed with deionized water(3×200 mL) and further dried by vacuum on the filter for 1 hour, beforebeing transferred to a vacuum oven and dried at 40° C. under housevacuum (˜28 mmHg (3.73 kPa)). The solid material was analyzed by HPLC.The analysis showed that the solid material contained 95.96%oxymorphone, based on HPLC area percent, 3100 ppm 14-hydroxymorphinone,based on HPLC area percent, and 19600 ppm 8-hydroxyoxymorphone, based onHPLC area percent.

About 6.94 molar equivalents of formic acid per molar equivalent oforipavine were used in Example 3, i.e. during the oxidation. No sulfuricacid was used. No precipitation was observed up to step 8 of Example 4.A molar excess of formic acid was present during the hydrogenation.

Comparative Example 5 Preparation of 14-Hydroxymorphinone Sulfate

1. Oripavine (30.0 g, 101 mmol) was charged as a slurry in deionizedwater (45 mL) into a 300 mL jacketed vessel, overhead stirred andequipped with a temperature probe and an addition funnel.

2. The jacket temperature for the vessel was set to 22° C., and theslurry was stirred at 500 rpm.

3. Formic acid (30 mL, 700 mmol) was added into the vessel. The solidsreadily dissolved into solution upon addition of formic acid. During theformic acid addition, the temperature of the reaction mixture increasedto 30° C.

4. Sulfuric acid (2.5 mL, 45 mmol) was added to the solution, and thesolution was stirred at 500 rpm.

5. After the solution temperature had cooled below 25° C., hydrogenperoxide (10.25 mL, 119 mmol) was added to the reaction through theaddition funnel at a rate of 0.17 mL/minute.

6. After the hydrogen peroxide addition was complete, an additional 5 mLof deionized water was added to the reaction through the additionfunnel, and the reaction solution was allowed to stir (500 rpm) at 22°C., and the reaction progress was monitored by HPLC. After stirring for20 hours, approximately 15-20% of the oripavine was still present in thereaction mixture, based on HPLC area %.

7. The reaction mixture was heated to 30° C. and an additional 1.5 mL(17 mmol) of hydrogen peroxide was added to the reaction in one portion,to increase conversion of oripavine (greater than 99% conversion, asdetermined by HPLC).

8. The reaction mixture was stirred (500 rpm) at 30° C. for anadditional 16 hours.

9. Sulfuric acid (0.35 mL, 6.3 mmol) was added into the reaction, andthe solution was stirred (500 rpm) for 10 minutes.

10. Methanol (60 mL) was added into the reaction mixture, and the rateof stirring was reduced to 200 rpm.

11. The reaction mixture was cooled to 15° C. over 2.5 hours. Uponcooling, solids precipitated out of the solution forming a suspension.

12. The resulting suspension was stirred (200 rpm) at 15° C. for anadditional 1 hour.

13. The solids were filtered under vacuum using a Buchner funnel, withWhatman# 1 filter paper, and the solids were collected and washed withmethanol (2×60 mL). A sample of the solids was analyzed by the HPLCmethod of Example 11A, and was shown to contain 14-hydroxymorphinonewith 349 ppm of 8-hydroxyoxymorphone (based on HPLC area percent).

14. The solids were dried under vacuum on the Buchner funnel for 30minutes, before being transferred to a drying oven and dried undervacuum to a constant weight. The solids contained 18.09 g (26 mmol(calculated without water of crystallization), 51.5% yield) of14-hydroxymorphinone sulfate as fine yellow crystals, containing 349 ppmof 8-hydroxyoxymorphone (based on HPLC area percent in relation to14-hydroxymorphinone).

15. To see whether the yield can be increased, the filtrate and methanolwashes were returned to the jacketed vessel and tert-butyl methyl ether(60 mL) was added to the mixture. Upon addition of the tert-butyl methylether, solids precipitated out of the reaction mixture. The mixture wasstirred at 200 rpm and heated to 55° C.

16. After the solids had completely dissolved, the solution wasgradually cooled to 20° C. over 3 hours. The mixture was stirred (200rpm) at 20° C. for an additional 48 hours. Upon cooling and stirring,solids precipitated.

17. The solids were filtered under vacuum using a Buchner funnel, withWhatman# 2 filter paper, washed with tert-butyl methyl ether (60 mL) anddried under vacuum on the Buchner funnel for 30 minutes, before beingtransferred to a drying oven and dried under vacuum to a constantweight. The solids contained 5.60g (8 mmol (calculated without water ofcrystallization), 15.8% yield) of 14-hydroxymorphinone sulfate as tancrystals. The composition of the tan crystals was substantially the sameas the composition of the yellow crystals isolated initially, exceptthat it contained 2051 ppm, based on HPLC area percent, of8-hydroxyoxymorphone.

About 7.4 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:13.6. Precipitation was observed in step 11.

Comparative Example 6 Preparation of Oxymorphone Free Base

1. 14-Hydroxymorphinone sulfate (11.95 g, 17.2 mmol (calculated withoutwater of crystallization)) (i.e., solids from the first isolation ofExample 5 (yellow crystals)), deionized water (120 mL) and methanol (48mL) were charged into a 250 mL flask equipped with a magnetic stir bar.The majority of solids did not dissolve into solution at roomtemperature.

2. Formic acid (1.50 mL, 40 mmol) was added to the mixture, and themixture was stirred vigorously at 22° C. After 30 minutes of stirring at22° C., a large portion of the solid material remained insoluble.

3. The mixture was transferred from the flask to a high pressurereaction vessel equipped with a magnetic stir bar. Into the vessel wascharged 5% palladium on carbon (0.091 g) and the vessel was sealed.

4. The mixture was stirred at 750 rpm and heated to 40° C. The mixturewas hydrogenated at 60 psia (413.69 kPa) for 6 hours.

5. The reaction was vented, purged with nitrogen, vented andhydrogenated at 60 psia (413.69 kPa) for an additional 3 hours.

6. The reaction was vented, purged with nitrogen and cooled to 22° C.over 8 hours.

7. The reaction mixture was filtered through filter paper to remove thepalladium on carbon and the filtrate was sampled for HPLC analysis. Thesolution pH was 2.75. Analysis by the HPLC method of Example 11A showedthat the sample contained oxymorphone free base with 72 ppm of8-hydroxyoxymorphone (based on HPLC area percent in relation tooxymorphone free base) and 62 ppm of 14-hydroxymorphinone (based on HPLCarea percent).

8. While stirring at 200 rpm, the solution was basified by adding 7 mLof 28% ammonium hydroxide to the filtrate solution; solids precipitatedout of solution during the ammonium hydroxide addition and the final pHof the mixture was 9.06. Solids were isolated, dried at room temperatureunder vacuum and sampled by the HPLC method of Example 11A. Analysis byHPLC showed that the solid sample contained oxymorphone free base with33 ppm of 8-hydroxyoxymorphone (based on HPLC area percent) and 17 ppmof 14-hydroxymorphinone (based on HPLC area percent).

9. The mixture was allowed to stir (200 rpm) at 22° C. for an additional30 minutes.

10. The solids were filtered under vacuum using a Buchner funnel, withWhatman# 2 filter paper, washed with water (2×12 mL) and dried undervacuum on the Buchner funnel for 30 minutes, before being transferred toa drying oven and dried under vacuum to a constant weight at 80° C. for16 hours. The solids contained 7.89 g (26.2 mmol, 76% yield) ofoxymorphone (base) as a white crystalline powder, 52 ppm of8-hydroxyoxymorphone and 41 ppm of 14-hydroxymorphinone, based on theHPLC method of Example 11A.

About 7.4 molar equivalents of total acid per molar equivalent oforipavine were used in Example 5, i.e. during the oxidation. The molarratio of sulfuric acid to formic acid was about 1:13.6 during oxidation.A molar excess of formic acid was present during the hydrogenation.

Synthetic Example 7 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. Into a 100 mL reaction vessel equipped with a temperature probe,overhead stirrer and reflux condenser, oripavine (3.02 g, 10.2 mmol) wascharged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Into the reaction was added 88% formic acid (6 mL, 139.9 mmol), andthe solids readily dissolved into solution. During the formic acidaddition, the temperature of the reaction mixture increased to 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours.

6. Stirring of the mixture was reduced to 75 rpm and the mixture wascooled to 0° C. over 1 hour. Solids began precipitating out of solutionafter the temperature of the mixture reached 15° C.

7. The mixture was stirred for an additional 1 hour at 0° C. The solidswere filtered under vacuum using a Buchner funnel with Whatman #1 filterpaper, and the filtered solids were washed with tert-butyl methyl ether(3×15 mL).

8. Additional solids precipitated out of the filtrate after thetert-butyl methyl ether washes were combined with the filtrate. Thesesolids were also filtered under vacuum using a Buchner funnel withWhatman #1 filter paper.

9. The two batches of solids were dried separately under vacuum on theBuchner funnel for 1 hour.

10. The solids were further dried in a vacuum oven at 80° C. for 16hours.

11. Isolated: 0.09 g of solid (14-hydroxymorphinone sulfate) from thefirst filtration with an HPLC peak area ratio of14-hydroxymorphinone:8-hydroxyoxymorphone equal to 6,340,697:312 (49.2ppm of 8-hydroxyoxymorphone), based on the HPLC method of Example 11A.The auto-scaled chromatograph of the sample is depicted in FIG. 3 ofPCT/IB2013/001541.

12. Isolated: 2.33 g of solid from the second filtration with an HPLCpeak area ratio of 14-hydroxymorphinone:8-hydroxyoxymorphone equal to5,672,733:1,561 (275 ppm 8-hydroxyoxymorphone, based on HPLC areapercent), based on the HPLC method of Example 11A. The auto-scaledchromatograph of the sample is depicted in FIG. 4 of PCT/IB2013/001541.

About 14.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:17.1. Precipitation was observed in step 6.

Synthetic Example 8 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. Into a 100 mL jacketed vessel equipped with a temperature probe,overhead stirrer and an addition funnel, oripavine (20.0 g, 67.4 mmol)was charged as a slurry in deionized water (30 mL).

2. The jacket temperature for the vessel was set to 20° C. and theslurry was stirred at 300 rpm.

3. 88% formic acid (10 mL, 232 mmol) was added into the reactionmixture. The solids readily dissolved into solution upon this addition.During the formic acid addition, the temperature of the reaction mixtureincreased to 30° C.

4. Sulfuric acid (2.0 mL, 36 mmol) was added to the solution, and thesolution was stirred at 300 rpm.

5. After the solution temperature had cooled below 25° C., 35% hydrogenperoxide (7.00 mL, 81.4 mmol) was added to the reaction over 15 minutes,using the addition funnel.

6. After the peroxide addition was complete, an additional 3 mL ofdeionized water was added to the reaction through the addition funnel.

7. The reaction solution was allowed to stir (300 rpm) at 20° C. for 20minutes.

8. The reaction was then heated to 30° C. and held at 30° C., whilestirring at 300 rpm for 8 hours.

9. The reaction mixture was then cooled to 20° C. over 2 hours andstirred (300 rpm) for an additional 8 hours at this temperature. Solidsprecipitated out of solution during the cooling from 30° C. to 20° C.

10. The resulting suspension was treated with 20 mL of methanol and thesuspension was stirred at 20° C. for 30 minutes.

11. The solids were filtered under vacuum using a Buchner funnel withWhatman #1 filter paper, and the solids were washed with methanol (2×20mL).

12. The solids were dried under vacuum on the Buchner funnel for 1 hour,before being transferred to a drying oven and dried under vacuum at 80°C. for 16 hours.

13. 7.19 g of solid (26 mmol (calculated without water ofcrystallization) 14-hydroxymorphinone sulfate (73.2% yield)) wasisolated as fine yellow-white crystals and analyzed by the HPLC methodof Example 11A. Analysis showed an HPLC area ratio of14-hydroxymorphinone:8-hydroxyoxymorphone of 8,873,042: 623. In otherwords, the composition comprised 97.88% 14-hydroxymorphinone (based onHPLC area percent) and 70 ppm 8-hydroxyoxymorphone (based on HPLC areapercent). The auto-scaled chromatograph and peak results from thisanalysis are depicted in FIG. 5 of PCT/IB2013/001541.

About 4.66 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:6.4. Precipitation was observed in step 9.

As compared to the previous example (Example 7), less total acid (formicacid plus sulfuric acid) was used (4.66 equivalents vs. 14.5equivalents), more sulfuric acid per formic acid was used (1:6.4 vs.1:17.1) and the conditions of the present reaction resulted in betteryield (73.2% vs. 67% 14-hydroxymorphinone sulfate).

Comparative Example 9 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows.

1. Into an 80 mL reaction vessel equipped with a temperature probe andmagnetic stirrer, oripavine (10.0 g, 33.7 mmol) was dissolved indeionized water (20 mL) and 88% formic acid (3.60 mL, 84.0 mmol).

2. The solution was stirred (600 rpm) at 22° C. for 15 minutes.

3. Sulfuric acid (0.94 mL, 17 mmol) was added into the reaction mixture,and the solution was stirred at 600 rpm. After the solution temperaturehad cooled below 25° C., 35% hydrogen peroxide (3.20 mL, 37.2 mmol) wasadded to the reaction in one portion.

4. After the peroxide addition was complete, an additional 1 mL ofdeionized water was added to the reaction. The reaction solution wasallowed to stir (600 rpm) at 22° C. for 60 minutes.

5. The reaction was then heated to 30° C. over 20 minutes and held at30° C., while stirring at 600 rpm for 16 hours.

6. Solids started to precipitate out of solution while stirring at 30°C.

7. The reaction mixture was then cooled to 22° C.

8. The resulting suspension was treated with 20 mL of methanol and thesuspension was stirred at 22° C. for 5 minutes.

9. The solids were filtered under vacuum using a Buchner funnel withWhatman #1 filter paper, and the solids were washed with methanol (2×10mL).

10. The solids were dried under vacuum on the Buchner funnel for 30minutes, before being transferred to a drying oven and dried undervacuum at 80° C. for 16 hours.

11. 8.08 g (11.6 mmol (calculated without water of crystallization),68.8% yield) of 14-hydroxymorphinone sulfate was isolated as fineyellow-white crystals. Analysis by the HPLC method of Example 11A showedan HPLC area ratio of 14-hydroxymorphinone:8-hydroxyoxymorphone of8,743,438:885. In other words, the mixture contained 101 ppm8-hydroxyoxymorphone. The auto-scaled chromatograph and peak resultsfrom this analysis are depicted in FIG. 6 of PCT/IB2013/001541.

About 3 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:5. Precipitation was observed in step 6.

The resulting 14-hydroxymorphinone sulfate was used as starting materialin the subsequent Example 10.

Comparative Example 10 Preparation of Oxymorphone from14-Hydroxymorphinone Sulfate

1. Into a 300 mL hydrogenation vessel equipped with a magnetic stir bar,14-hydroxymorphinone sulfate obtained in Example 9 above (7.03 g, 10.1mmol (calculated without water of crystallization)), deionized water (70mL) and methanol (28 mL) were charged. The majority of solids dissolvedinto solution.

2. Formic acid (0.935 mL, 21.8 mmol) and 5% palladium on carbon (0.053g) were added into the reaction mixture.

3. The vessel was sealed, stirred at 750 rpm and heated to 40° C.

4. The mixture was then hydrogenated at 60 psia (413.69 kPa) for 5hours.

5. The reaction was vented, purged with nitrogen, vented andhydrogenated at 60 psia (413.69 kPa) for an additional 1 hour.

6. The reaction was vented, purged with nitrogen and cooled to 22° C.over 8 hours.

7. The reaction mixture was filtered through filter paper to remove thepalladium on carbon and the filtrate was sampled for the HPLC analysisof Example 11A. The results showed that less than 1%14-hydroxymorphinone (free base) remained (by HPLC area %).

8. The filtrate was transferred to a 250 mL Erlenmeyer flask equippedwith a magnetic stir bar and pH probe. The solution pH was 2.66.

9. While stirring at 200 rpm, the solution was basified by adding 5 mLof 28% ammonium hydroxide; solids precipitated out of solution duringthe ammonium hydroxide addition and the final pH of the mixture was9.13.

10. The mixture was allowed to stir (200 rpm) at 22° C. for anadditional 45 minutes.

11. The solids were filtered under vacuum using a Buchner funnel withWhatman# 2 filter paper, and the solids were washed with water (2×10mL).

12. The solids were dried under vacuum on the Buchner funnel for 2hours, before being transferred to a drying oven and dried under vacuumto a constant weight.

13. Isolated: 4.58 g (15.2 mmol, 75% yield) of oxymorphone (base) as awhite crystalline powder as analyzed by the HPLC method of Example 11A.The HPLC area ratio of oxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone was 39,612,808:231 (6ppm):9,518 (240 ppm). In other words, the composition contained 98.54%oxymorphone base, 6 ppm 14-hydroxymorphinone, and 240 ppm8-hydroxyoxymorphone, based on HPLC area percent. The auto-scaledchromatograph and peak results from this analysis are depicted in FIG.3.

Over all, about 3.64 molar equivalents of total acid per molarequivalent of oripavine were used in Examples 9 and 10. A molar excessof formic acid was present during the hydrogenation.

Example 11 HPLC Method Example 11A

HPLC conditions for Examples 1 to 10 and 12 to 15 were as follows:

-   -   Instrument: Waters 2695 HPLC system with Waters 966 Photodiode        Array Detector    -   Column: Waters XBridge C18 (150×3.0 mm; 3.5 μm)    -   Mobile phase:        -   Solution A: 10 mMol (pH=10.2) ammonium bicarbonate in water        -   Solution B: methanol    -   Flow rate: 0.30 mL/min    -   UV detection: 292 nm    -   Injection volume: 10 μl of a 1 mg/mL sample solution. Samples        were prepared by weighing 10±0.5 mg of sample and quantitatively        transferring it to a 10 mL volumetric flask. The solids were        dissolved in a 80:20 mixture of 0.085% phosphoric acid in        water:methanol.    -   Column temperature: 30° C.    -   Run Time: 42 minutes

Gradient Conditions (Linear Concentration Changes):

TABLE 1 Time Flow % A % B initial 0.30 90.0 10.0  1.00 0.30 90.0 10.0 5.00 0.30 78.0 22.0 16.00 0.30 60.0 40.0 22.00 0.30 53.0 47.0 26.000.30 48.0 52.0 31.90 0.30 25.0 75.0 32.20 0.30 90.0 10.0 42.00 0.30 90.010.0

A representative HLPC chromatogram showing all relevant peaks isprovided in FIG. 4. The components corresponding to the peaks are givenin Table 2.

TABLE 2 Peak Retention Components Abbreviations Time RRT14-Hydroxymorphinone N-Oxide FHM-N-Oxide 3.227 0.1510-Hydroxyoxymorphone 10OH-OMN 10.767 0.50 8-Hydroxyoxymorphone 8OH-OMN14.641 0.68 14-Hydroxymorphinone FHM 17.544 0.82 HydromorphoneHydromorphone 19.120 0.89 Oxymorphone OMN 21.461 1.00 6β-Oxymorphol6bOH-OMN 22.485 1.04 6α-Oxymorphol 6aOH-OMN 23.451 1.09 Oripavine ORP23.794 1.11 8,14-Dihydrooripavine 8,14-DHO 26.385 1.23 Oxycodone OXY31.228 1.46The relative retention time (RRT) was calculated in relation tooxymorphone.

-   Estimated LOD was 1 ppm, estimated LOQ was 3 to 5 ppm.

Example 11B

HPLC conditions for Examples 16 to 17 were as follows:

-   -   HPLC unit: Agilent 1100 series HPLC    -   Detectors: Agilent 1100 Series DAD UV detector        -   HP 1100 MSD mass detector    -   Column: Waters XSelect C18, 150×3.0 mm, 3.5 μm    -   Mobile phase:        -   Solution A: 10 mMol (pH=10.2) ammonium bicarbonate in water        -   Solution B: methanol    -   Flow rate: 0.30 mL/min    -   UV detection: 292 nm    -   Injection volume: 5 μl of a 1 mg/mL or 10 mg/mL sample solution.        Samples were prepared by weighing 100±5 mg or 10±0.5 mg of        sample and quantitatively transferring it to a 10 mL volumetric        flask. The solids were dissolved in a 80:20 mixture of 0.085%        phosphoric acid in water: methanol.    -   Column temperature: 30° C.    -   Run Time: 37 minutes

Gradient Conditions (Linear Concentration Changes):

TABLE 3 Time Flow % A % B initial 0.30 90.0 10.0  1.00 0.30 90.0 10.0 5.00 0.30 78.0 22.0 16.00 0.30 60.0 40.0 22.00 0.30 53.0 47.0 26.000.30 48.0 52.0 31.90 0.30 25.0 75.0 37.00 0.30 25.0 75.0

A representative HLPC chromatogram showing all relevant peaks isprovided in FIG. 5. The components corresponding to the peaks are givenin Table 4.

TABLE 4 Peak Retention Components Abbreviations mass Time RRT8-Hydroxyoxymorphone 8OH-OMN 317 + 1 15.36 0.69 14-Hydroxymorphinone FHM299 + 1 18.31 0.82 14-Hydroxymorphine 6aOH-FHM 301 + 1 19.95 0.90Oxymorphone OMN 301 + 1 22.25 1.00 6α-Oxymorphol 6aOH-OMN 303 + 1 24.411.10 Oripavine ORP 297 + 1 26.59 1.20The relative retention time (RRT) was calculated in relation tooxymorphone.

-   Estimated LOD was 1 ppm, estimated LOQ was 3 to 5 ppm.

Synthetic Example 12 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a 250 mL 3-necked flask equipped with a temperature probe andmagnetic stirring bar, oripavine (10.0 g; 33.6 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Thesolution warmed up to 25° C. The solution was stirred (500 rpm) at 21°C. for 5 minutes.

2. Concentrated sulfuric acid (96%, 1.01 mL, 18.2 mmol) was added. Thetemperature rose to 35° C. The mixture was stirred (500 rpm) at 21° C.for 20 min.

3. Hydrogen peroxide (35 wt % in H₂O, 3.61 mL, 42.16 mmol) was added andthe solution stirred (500 rpm) for 30 minutes at room temperature.

4. The mixture was then heated to 35° C. over 5 minutes and held at 35°C. and stirred (500 rpm) for 48 hours. Solids started to precipitateduring the stirring after 10 hours.

5. To the resulting suspension was added 2-butanol (36 mL) and thestirring continued for 30 min. The temperature decreased from 35° C. to26° C. during this time. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (10.5 g, 15.1 mmol(calculated without water of crystallization) 90% yield). No oripavineor 8-hydroxyoxymorphone was detectable by HPLC.

About 3.54 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:5.5. Precipitation was observed in step 4.

As compared to the previous examples (Examples 7 and 8), less total acid(formic acid plus sulfuric acid) was used (3.54 equivalents vs. 14.5equivalents and 4.66 equivalents), more sulfuric acid per formic acidwas used (1:5.5 vs. 1:17.1 and 1:6.4), and the conditions of the presentreaction resulted in better yield (90% vs. 67% and 73.2%14-hydroxymorphinone sulfate).

Synthetic Example 13 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (9.96 g, 33.5 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Theresulting solution was stirred at ambient temperature.

2. Concentrated sulfuric acid (96%, 0.92 mL, 16.8 mmol) was added andthe mixture stirred at 450 rpm for 10 minutes. After addition of thesulfuric acid, the mixture heated to more than 30° C., then cooledagain.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.8 mL, 44 mmol) was added and thesolution stirred at 450 rpm for 20 minutes at room temperature.

4. The mixture was then stirred at 35° C. internal temperature for 48hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water: 2-butanol (1: 2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (9.94 g, 14.3 mmol(calculated without water of crystallization) 85.4% yield). No oripavineor 8-hydroxyoxymorphone was detectable by HPLC.

About 3.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:6.

In this example, 0.5 equivalents H₂SO₄ were used. As in Example 12(where 0.55 equivalents H₂SO₄ were used), compared to the previousexamples (Examples 7 and 8), less total acid (formic acid plus sulfuricacid) was used (3.5 equivalents vs. 14.5 equivalents and 4.66equivalents), more sulfuric acid per formic acid was used (1:6 vs.1:17.1 and 1:6.4), and the conditions of the present reaction resultedin better yield (85.4% vs. 67% and 73.2% 14-hydroxymorphinone sulfate).

Synthetic Example 14 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared using two different amounts ofwater as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (10.4 g, 35.0 mmol) was dissolved inde-ionized water (16 or 20 mL, respectively) and 98% formic acid (3.88mL, 101 mmol). The resulting solution was stirred at ambient temperature(500 rpm).

2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was added andthe mixture stirred at 500 rpm for 20 minutes. After addition of thesulfuric acid, the mixture heated to more than 30° C., then cooledagain.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.62 mL, 42 mmol) was added and thesolution stirred at 500 rpm for 30 minutes at room temperature.

4. The mixture was then stirred (750 rpm) at 35° C. internal temperaturefor 48 hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (9.90 g, 14.21mmol (calculated without water of crystallization) 81.2% yield for 16 mLwater; 10.14 g, 14.56 mmol (calculated without water of crystallization)83.2% yield for 20 mL water). No oripavine or 8-hydroxyoxymorphone wasdetectable by HPLC.

This Example shows the same advantages as pointed out in Example 12.Moreover, it shows that in addition to the 1.8 mL water per g oripavineas used in Example 12, 1.5 and 1.9 mL water per g oripavine can alsoadvantageously be used.

Synthetic Example 15 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (10.04 g, 33.8 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Theresulting solution was stirred (500 rpm) at ambient temperature.

2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was added andthe mixture stirred for about 20 minutes. After addition of the sulfuricacid, the mixture heated to more than 30° C., then cooled again.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.46 mL, 40.1 mmol, corresponding to1.2 eq.) was added and the solution stirred for 30 minutes at roomtemperature.

4. The mixture was then stirred at 35° C. internal temperature for 48hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (10.07 g, 14.5mmol (calculated without water of crystallization) 85.8% yield). Nooripavine or 8-hydroxyoxymorphone was detectable by HPLC.

As in Example 12 (where 1.25 equivalents of hydrogen peroxide wereused), compared to the previous examples (Examples 7 and 8), less totalacid (formic acid plus sulfuric acid) was used (3.55 equivalents vs.14.5 equivalents and 4.66 equivalents), more sulfuric acid per formicacid was used (1:5.5 vs. 1:17.1 and 1:6.4), and the conditions of thepresent reaction resulted in better yield (85.8% vs. 67% and 73.2%14-hydroxymorphinone sulfate).

Example 16 Hydrogenation of 14-Hydroxymorphinone Sulfate in the Presenceof Trifluoroacetic Acid and Propylene Glycol

14-hydroxymorphinone sulfate (23.05 g, 66.19 mmol free14-hydroxymorphinone, containing 0.17% 8-hydroxyoxymorphone) and Pd/C(70 mg, 5% Pd, 50% wet, Escat test kit 1471, Strem) were suspended in amixture of water (90 mL) and propylene glycol (60 mL) in a 3L flask. Tothis was added trifluoroacetic acid (2.0 mL, 26.12 mmol) and the mixturewas hydrogenated with an overhead mounted balloon of hydrogen (ambientpressure, 14.7 psia) for 20 h at 34° C. and 1100 rpm stirring with astirring bar. HPLC analysis according to Example 11B showed completeconversion. To the mixture was added more Pd/C (70 mg, same batch asabove) and the hydrogenation was continued for 6 h at 34° C. until theresult of the above mentioned HPLC analysis was known.

The mixture was filtered over Celite, washed with water (30 mL) and thefiltrate basified with conc. aq. sodium hydroxide (30% w/w, ca. 8.5 mL)to pH 9. After cooling to 5° C. for 16h the mixture was filtered and thesolids washed with 65% 2-butanol/water (2×30 mL), then 2-butanol (30mL).

Drying in vacuo afforded oxymorphone (13.3 g, 67%) in 96.6% purity(average of 3 analyses, 0.26% standard deviation). No propylene glycolacetal, 14-hydroxymorphinone or 8-hydroxyoxymorphone were detectable in1 mg/mL samples. Further analysis of highly concentrated (10 mg/mL, outof linearity range) samples detected no 8-hydroxyoxymorphone and no14-hydroxymorphinone as well.

Example 17 Hydrogenation of 14-Hydroxymorphinone Sulfate in the Presenceof Trifluoroacetic Acid and Ethylene Glycol

14-hydroxymorphinone sulfate (4.72 g, containing 15% water, 11.51 mmolfree 14-hydroxymorphinone) and Pd/C (17 mg, 5% Pd, 50% wet, Escat testkit 1471, Strem) were suspended in a mixture of water (17.3 mL) andethylene glycol (11 mL) in a 250 mL flask. To this was addedtrifluoroacetic acid (0.37 mL, 4.74 mmol) and the mixture hydrogenatedwith an overhead mounted balloon of hydrogen (ambient pressure, 14.7psia) for 20 h at 30° C. and 750 rpm stirring with a stirring bar. HPLCanalysis according to Example 11B showed complete conversion with 0.23%of formed ethylene glycol acetal. The mixture was filtered over Celite,washed with water (5 mL) and the filtrate basified with conc. aq. sodiumhydroxide (30% w/w, ca. 1.5 mL) to pH 9-9.5. After cooling to 5° C. for2 h the mixture was filtered and the solids washed with 20%2-butanol/water (10 mL).

Drying in vacuo afforded oxymorphone (2.70 g, 8.97 mmol, 78%) in 99%purity. No ethylene glycol acetal, 14-hydroxymorphinone or8-hydroxyoxymorphone were detectable.

In the preceding specification, the invention has been described withreference to specific exemplary embodiments and examples thereof. Itwill, however, be evident that various modifications and changes may bemade thereto without departing from the broader spirit and scope of theinvention as set forth in the claims that follow. The specification anddrawings are accordingly to be regarded in an illustrative manner ratherthan a restrictive sense.

The invention claimed is:
 1. A process for preparing oxymorphone or asalt or solvate thereof from a 14-hydroxymorphinone salt or a solvatethereof

the process comprising the steps of (a) providing a solution orsuspension of the 14-hydroxymorphinone salt or a solvate thereof; (b)adding trifluoroacetic acid and/or a glycol; and (c) reducing the14-hydroxymorphinone present in the solution or suspension to theoxymorphone by hydrogenation, wherein X^(n−) is an anion selected fromthe group consisting of Cl⁻, HSO₄ ⁻, SO₄ ²⁻, methanesulfonate, tosylate,trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻, PO₄ ³⁻, oxalate, perchlorate, andany mixtures thereof; and n is 1,2, or
 3. 2. The process of claim 1,wherein trifluoroacetic acid and the glycol are added in step (b). 3.The process of claim 1, wherein n is 2 and X^(n−) is SO₄ ²⁻.
 4. Theprocess of claim 1, wherein the amount of trifluoroacetic acid is 99 mol% or less as compared to the molar amount of 14-hydroxymorphinonecontained in the 14-hydroxymorphinone salt.
 5. The process of claim 4,wherein the amount of trifluoroacetic acid is from 30 mol % to 50 mol %as compared to the molar amount of 14-hydroxymorphinone contained in the14-hydroxymorphinone salt.
 6. The process of claim 1, wherein the glycolis selected from the group consisting of ethylene glycol, propyleneglycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol,neopentylglycol, and mixtures thereof.
 7. The process of claim 6,wherein the glycol is ethylene glycol, propylene glycol, or a mixturethereof.
 8. The process of claim 1, wherein the glycol added in step (b)is in the range of from 1 to 8 volumes/weight calculated from the glycolvolume in mL in relation to the weight in grams of the14-hydroxymorphinone salt.
 9. The process of claim 1, wherein thehydrogenation in step (c) is performed with H₂ and a hydrogenationcatalyst.
 10. The process of claim 1, wherein a mixture of water and theglycol is used as solvent, wherein the mixture is in a range from 20:80to 45:55 glycol:water.
 11. The process of claim 1, additionallycomprising the step: (d) adding a base, thus raising the pH to a pHwhere the oxymorphone precipitates as its free base, and isolating theoxymorphone as its free base or a solvate thereof.
 12. The process ofclaim 11, wherein the base added in step (d) is NaOH.